Quinazoline compounds

ABSTRACT

Quinazoline derivatives of formula (I) wherein A is 5-membered heteroaryl containing a sulphur atom and optionally containing one or more nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.

The present invention relates to certain quinazoline derivatives for usein the treatment of certain diseases in particular to proliferativedisease such as cancer and in the preparation of medicaments for use inthe treatment of proliferative disease, to novel quinazoline compoundsand to processes for their preparation, as well as pharmaceuticalcompositions containing them as active ingredient.

Cancer (and other hyperproliferative disease) is characterised byuncontrolled cellular proliferation. This loss of the normal regulationof cell proliferation often appears to occur as the result of geneticdamage to cellular pathways that control progress through the cellcycle.

In eukaryotes, an ordered cascade of protein phosphorylation is thoughtto control the cell cycle. Several families of protein kinases that playcritical roles in this cascade have now been identified. The activity ofmany of these kinases is increased in human tumours when compared tonormal tissue. This can occur by either increased levels of expressionof the protein (as a result of gene amplification for example), or bychanges in expression of co activators or inhibitory proteins.

The first identified, and most widely studied of these cell cycleregulators have been the cyclin dependent kinases (or CDKs). Activity ofspecific CDKs at specific times is essential for both initiation andcoordinated progress through the cell cycle. For example, the CDK4protein appears to control entry into the cell cycle (the G0-G1-Stransition) by phosphorylating the retinoblastoma gene product pRb. Thisstimulates the release of the transcription factor E2F from pRb, whichthen acts to increase the transcription of genes necessary for entryinto S phase. The catalytic activity of CDK4 is stimulated by binding toa partner protein, Cyclin D. One of the first demonstrations of a directlink between cancer and the cell cycle was made with the observationthat the Cyclin D1 gene was amplified and cyclin D protein levelsincreased (and hence the activity of CDK4 increased) in many humantumours (Reviewed in Sherr, 1996, Science 274: 1672-1677; Pines, 1995,Seminars in Cancer Biology 6: 63-72). Other studies (Loda et al., 1997,Nature Medicine 3(2): 231-234; Gemma et al., 1996, International Journalof Cancer 68(5): 605-11; Elledge et al. 1996, Trends in Cell Biology 6;388-392) have shown that negative regulators of CDK function arefrequently down regulated or deleted in human tumours again leading toinappropriate activation of these kinases.

More recently, protein kinases that are structurally distinct from theCDK family have been identified which play critical roles in regulatingthe cell cycle and which also appear to be important in oncogenesis.These include the newly identified human homologues of the Drosophilaaurora and S. cerevisiae Ip11 proteins. The three human homologues ofthese genes Aurora-A, Aurora-B and Aurora-C (also known as aurora2,aurora1 and aurora3 respectively) encode cell cycle regulatedserine-threonine protein kinases (summarised in Adams et al., 2001,Trends in Cell Biology. 11(2): 49-54). These show a peak of expressionand kinase activity through G2 and mitosis. Several observationsimplicate the involvement of human aurora proteins in cancer. TheAurora-A gene maps to chromosome 20q13, a region that is frequentlyamplified in human tumours including both breast and colon tumours.Aurora-A may be the major target gene of this amplicon, since Aurora-ADNA is amplified and mRNA overexpressed in greater than 50% of primaryhuman colorectal cancers. In these tumours Aurora-A protein levelsappear greatly elevated compared to adjacent normal tissue. In addition,transfection of rodent fibroblasts with human Aurora-A leads totransformation, conferring the ability to grow in soft agar and formtumours in nude mice (Bischoff et al., 1998, The EMBO Journal. 17(11):3052-3065). Other work (Zhou et al., 1998, Nature Genetics. 20(2):189-93) has shown that artificial overexpression of Aurora-A leads to anincrease in centrosome number and an increase in aneuploidy, a knownevent in the development of cancer. Further work has shown an increasein expression of Aurora-B (Adams et al., 2001, Chromsoma. 110(2):65-74)and Aurora-C (Kimura et al., 1999, Journal of Biological Chemistry,274(11): 7334-40) in tumour cells when compared to normal cells.

Importantly, it has also been demonstrated that abrogation of Aurora-Aexpression and function by antisense oligonucleotide treatment of humantumour cell lines (WO 97/22702 and WO 99/37788) leads to cell cyclearrest and exerts an antiproliferative effect in these tumour celllines. Additionally, small molecule inhibitors of Aurora-A and Aurora-Bhave been demonstrated to have an antiproliferative effect in humantumour cells (Keen et al. 2001, Poster #2455, American Association ofCancer research annual meeting), as has selective abrogation of Aurora-Bexpression alone by siRNA treatment (Ditchfield et al. 2003. Journal ofCell Biology, 161(2): 267-280). This indicates that inhibition of thefunction of Aurora-A and/or Aurora-B will have an antiproliferativeeffect that may be useful in the treatment of human tumours and otherhyperproliferative disease. Further, inhibition of Aurora kinases as atherapeutic approach to these diseases may have significant advantagesover targeting signalling pathways upstream of the cell cycle (e.g.those activated by growth factor receptor tyrosine kinases such asepidermal growth factor receptor (EGFR) or other receptors). Since thecell cycle is ultimately downstream of all of these diverse signallingevents, cell cycle directed therapies such as inhibition of Aurorakinases would be predicted to be active across all proliferating tumourcells, whilst approaches directed at specific signalling molecules (e.g.EGFR) would be predicted to be active only in the subset of tumour cellswhich express those receptors. It is also believed that significant“cross talk” exists between these signalling pathways meaning thatinhibition of one component may be compensated for by another.

A number of quinazoline derivatives have been proposed hitherto for usein the inhibition of various kinases. For example, WO 96/09294, WO96/15118 and WO 99/06378 describe the use of certain quinazolinecompounds as receptor tyrosine kinase inhibitors, which may be useful inthe treatment of proliferative disease and WO 00/21955 discloses certainquinazoline derivatives as inhibitors of the effects of VEGF.

Quinazoline derivatives have also been disclosed for use in theinhibition of Aurora-A kinase. WO 02/00649 discloses quinazolinederivative bearing a 5-membered heteroaromatic ring where the ring is,in particular, substituted thiazole or substituted thiophene. Howeverdespite the compounds of WO 02/00649 there still exists the need forfurther compounds having Aurora kinase inhibitory properties.

The applicants have been successful in finding a novel series ofcompounds which inhibit the effects of the Aurora kinases and inparticular Aurora-A and/or Aurora-B kinase and which have certainproperties that make them particularly useful in formulating medicamentsfor the treatment of disease. In particular the compounds are of use inthe treatment of proliferative disease such as cancer, occurring aseither solid and haematogocial tumours where Aurora kinases are known tobe active and especially in diseases such as colorectal, breast, lung,prostate, pancreatic or bladder and renal cancer as well as leukemiasand lymphomas.

According to one aspect of the present invention there is provided acompound of formula (I):

wherein A is 5-membered heteroaryl containing a sulphur atom andoptionally containing one or more nitrogen atoms;

-   X is O, S, S(O), S(O)₂ or NR¹⁴;-   m is 0, 1, 2or 3;-   Z is a group selected from —NR¹R², phosphonooxy, C₃₋₆cycloalkyl    which C₃₋₆cycloalkyl is substituted by phosphonooxy or C₁₋₄alkyl    substituted by phosphonooxy, and a 4- to 7-membered ring linked via    a carbon atom, containing a nitrogen atom and optionally containing    a further nitrogen atom which ring may be saturated, unsaturated or    partially saturated, wherein the ring is substituted on carbon or    nitrogen by phosphonooxy or C₁₋₄alkyl substituted by phosphonooxy    and wherein the ring is optionally further substituted on carbon or    nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups;-   R¹ is a group selected from —COR⁸, —CONR⁸R⁹ and C₁₋₆alkyl which    C₁₋₆alkyl is substituted by phosphonooxy and optionally further    substituted by 1 or 2 halo or methoxy groups;-   R² is a group selected from hydrogen, —COR¹⁰, —CONR¹⁰R¹¹ and    C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1, 2, or 3    halo or C₁₋₄alkoxy groups or —S(O)_(p)R¹¹ (where p is 0, 1 or 2) or    phosphonooxy, or R² is a group selected from C₂₋₆alkenyl,    C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl;-   or R¹ and R² together with the nitrogen to which they are attached    form a 4- to 7-membered ring optionally containing a further    nitrogen atom which ring may be saturated, unsaturated or partially    saturated, wherein the ring is substituted on carbon or nitrogen, by    a group selected from phosphonooxy and C₁₋₄alkyl which C₁₋₄alkyl is    substituted by phosphonooxy or —NR⁸R⁹, and where the ring is    optionally further substituted on carbon or nitrogen, by 1, 2 or 3    halo or C₁₋₄alkyl groups;-   R³ is a group selected from hydrogen, halo, cyano, nitro,    C₁₋₆alkoxy, C₁₋₆alkyl, —OR¹², —CHR¹²R¹³, —OC(O)R¹², —C(O)R¹²,    —NR¹²C(O)R¹³, C(O)NR¹²R¹³, —NR¹²SO₂R¹³ and —NR¹²R¹³;-   R⁴ is hydrogen or a group selected from C₁₋₄alkyl, heteroaryl,    heteroarylC₁₋₄alkyl, aryl and arylC₁₋₄alkyl which group is    optionally substituted by 1, 2 or 3 substitutents selected from    halo, methyl, ethyl, cyclopropyl and ethynyl;-   R⁵ is a group selected from hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl,    C₂₋₄alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl;-   R⁶ and R⁷ are independently selected from hydrogen, halo, C₁₋₄alkyl,    C₃₋₆cycloalkyl, hydroxy and C₁₋₄alkoxy;-   R⁸ is C₁₋₄alkyl substituted by phosphonooxy and optionally further    substituted by 1 or 2 halo or methoxy groups;-   R⁹ is a group selected from hydrogen and C₁₋₄alkyl;-   R¹⁰ is a group selected from hydrogen and C₁₋₄alkyl which C₁₋₄alkyl    is optionally substituted by halo, C₁₋₄alkoxy, S(O)_(q) (where q is    0, 1 or 2) or phosphonoxy;-   R¹¹, R¹², R¹³ and R¹⁴ are independently selected from hydrogen,    C₁₋₄alkyl or heterocyclyl;-   or a pharmaceutically acceptable salt thereof.

Within the present invention, it is to be understood that, insofar ascertain compounds of formula (I) herein defined may exist in opticallyactive or racemic forms by virtue of one or more asymmetric carbon orsulphur atoms, the invention includes in its definition any suchoptically active or racemic form which possesses Aurora kinaseinhibitory activity and in particular Aurora-A and/or Aurora-B kinaseinhibitory activity. The synthesis of optically active forms may becarried out by standard techniques of organic chemistry well known inthe art, for example by synthesis from optically active startingmaterials or by resolution of a racemic form. Similarly, theabove-mentioned activity may be evaluated using the standard laboratorytechniques referred to herein.

Within the present invention it is to be understood that a compound offormula (I) or a salt thereof may exhibit the phenomenon of tautomerismand that the formulae drawings within this specification can representonly one of the possible tautomeric forms. It is to be understood thatthe invention encompasses any tautomeric form which has Aurora kinaseinhibitory activity and in particular Aurora-A and/or Aurora-B kinaseinhibitory activity and is not to be limited merely to any onetautomeric form utilised within the formulae drawings.

It is also to be understood that certain compounds of formula (I) andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which have Aurora kinase inhibitoryactivity and in particular Aurora-A and/or Aurora-B kinase inhibitoryactivity.

The present invention relates to the compounds of formula (I) as hereindefined as well as to the salts thereof. Salts for use in pharmaceuticalcompositions will be pharmaceutically acceptable salts, but other saltsmay be useful in the production of the compounds of formula (I) andtheir pharmaceutically acceptable salts. Pharmaceutically acceptablesalts of the invention may, for example, include acid addition salts ofcompounds of formula (I) as herein defined which are sufficiently basicto form such salts. Such acid addition salts include but are not limitedto furmarate, methanesulphonate, hydrochloride, hydrobromide, citrateand maleate salts and salts formed with phosphoric and sulphuric acid.In addition where compounds of formula (I) are sufficiently acidic,salts are base salts and examples include but are not limited to, analkali metal salt for example sodium or potassium, an alkaline earthmetal salt for example calcium or magnesium, or organic amine salt forexample triethylamine, ethanolamine, diethanolamine, triethanolamine,morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine oramino acids such as lysine.

The compounds of formula (I) may also be provided as in vivohydrolysable esters. An in vivo hydrolysable ester of a compound offormula (I) containing carboxy or hydroxy group is, for example apharmaceutically acceptable ester which is cleaved in the human oranimal body to produce the parent acid or alcohol. Such esters can beidentified by administering, for example, intravenously to a testanimal, the compound under test and subsequently examining the testanimal's body fluid.

Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethylesters for example pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

Suitable pharmaceutically acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group/s. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy includeC₁₋₁₀alkanoyl, for example formyl, acetyl, benzoyl, phenylacetyl,substituted benzoyl and phenylacetyl; C₁₋₁₀alkoxycarbonyl (to give alkylcarbonate esters), for example ethoxycarbonyl; di-C₁₋₄alkylcarbamoyl andN-(di-C₁₋₄alkylaminoethyl)-N—C₁₋₄alkylcarbamoyl (to give carbamates);di-C₁₋₄alkylaminoacetyl and carboxyacetyl. Examples of ring substituentson phenylacetyl and benzoyl include aminomethyl, C₁₋₄alkylaminomethyland di-(C₁₋₄alkyl)aminomethyl, and morpholino or piperazino linked froma ring nitrogen atom via a methylene linking group to the 3- or4-position of the benzoyl ring. Other interesting in vivo hydrolysableesters include, for example, R^(A)C(O)OC₁₋₆alkyl-CO—, wherein R^(A) isfor example, benzyloxy-C₁₋₄alkyl, or phenyl. Suitable substituents on aphenyl group in such esters include, for example,4-C₁₋₄piperazino-C₁₋₄alkyl, piperazino-C₁₋₄alkyl andmorpholino-C₁₋₄alkyl.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for the straightchain version only and references to individual branched-chain alkylgroups such as “tert-butyl” are specific for the branched chain versiononly. An analogous convention applies to other generic terms, forexample “alkenyl” and “alkynyl”.

“Cycloalkyl” is a monocyclic, saturated alkyl ring and “aryl” is amonocyclic or bicyclic aromatic ring.

Unless otherwise specified “heteroaryl” is a monocyclic or bicyclicaromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ringatoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogenor sulphur may be oxidised.

“Heterocyclyl” is a saturated, unsaturated or partially saturated,monocyclic or bicyclic ring containing 4 to 12 atoms of which 1, 2, 3 or4 ring atoms are chosen from nitrogen, sulphur or oxygen, which ring maybe carbon or nitrogen linked, wherein a —CH₂— group can optionally bereplaced by a —C(O)—; wherein a ring nitrogen or sulphur atom isoptionally oxidised to form the N-oxide or S-oxide(s); wherein a ring—NH is optionally substituted by acetyl, formyl, methyl or mesyl; andwherein a ring is optionally substituted by one or more halo.

“Phosphonooxy” is in one aspect a group of formula —OP(O)(OH)₂. Howeverthe term “phosphonooxy” also includes salts of this group such as thoseformed with alkali metal ions such as sodium or potassium ions oralkaline earth metal ions, for example calcium or magnesium ions.

Where optional substituents are chosen from “1 or 2”, from “1, 2, or 3”or from “1, 2, 3 or 4” groups or substituents it is to be understoodthat this definition includes all substituents being chosen from one ofthe specified groups i.e. all substitutents being the same or thesubstituents being chosen from two or more of the specified groups i.e.the substitutents not being the same.

Compounds of the present invention have been named with the aid ofcomputer software (ACD/Name version 6.6 or ACD Name Batch version 6.0).

Suitable values for any R group (R¹ to R¹⁴) or any part or substitutentfor such groups include:

-   for C₁₋₄alkyl: methyl, ethyl, propyl, isopropyl, butyl,    2-methylpropyl and tert-butyl;-   for C₁₋₆alkyl: C₁₋₄alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl    and hexyl;-   for C₂₋₄alkenyl: vinyl, allyl and 1-propenyl;-   for C₂₋₆alkenyl: C₂₋₄alkenyl, 1-butenyl, 2-butenyl, 3-butenyl,    2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and    4-hexenyl;-   for C₂₋₄alkynyl: ethynyl, 1-propynyl, 2-propynyl and 3-butynyl;-   for C₂₋₆alkynyl: C₂₋₄alkynyl, 2-pentynyl, hexynyl and    1-methylpent-2-ynyl;-   for C₃₋₆cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   for C₃₋₆cycloalkylC₁₋₄alkyl: cyclopropylmethyl, cyclopropylethyl,    cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl;-   for aryl: phenyl and naphthyl;-   for arylC₁₋₄alkyl: benzyl, phenethyl, naphthylmethyl and    naphthylethyl;-   for halo: fluoro, chloro, bromo and iodo;-   for C₁₋₄alkoxy: methoxy, ethoxy, propoxy and isopropoxy;-   for C₁₋₆alkoxy: C₁₋₄alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy;-   for heteroaryl: pyridyl, imidazolyl, quinolinyl, cinnolyl,    pyrimidinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, triazolyl,    oxazolyl, isoxazolyl and pyrazinyl and preferably thiazolyl,    pyridyl, imidazolyl and pyrimidinyl;-   for heteroarylC₁₋₄alkyl: pyridylmethyl, pyridylethyl,    pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl,    imidazolylpropyl, imidazolylbutyl, quinolinylpropyl,    1,3,4-triazolylpropyl and oxazolylmethyl;-   for heterocyclyl: furyl, thienyl, pyrrolyl, pyrrolidinyl,    imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl,    pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,    quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl,    benzoxazolyl, benzothienyl, benzofuryl, piperidinyl,    N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl,    N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl,    oxetanyl, morpholinyl, tetrahydroisoquinolinyl,    tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl,    tetrahydrofuranyl, 2,5-dioximidazolidinyl,    2,2-dimethyl-1,3-dioxolanyl and 3,4-dimethylenedioxybenzyl.

It should be noted that examples given for terms used in the descriptionare not limiting.

Preferred values of A, X, m, Z, R³, R⁴, R⁵, R⁶ and R⁷ are as follows.Such values may be used where appropriate with any of the definitions,claims or embodiments defined herein.

In one aspect of the invention A is a thiazolyl, thiophenyl orthiadiazolyl. In a further aspect A is a group of formula (a), (b), (c),(d), (e) or (f):

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the (CR⁶R⁷) group of formula (I). Inanother aspect A is a group of formula (a) as defined above.

In one aspect of the invention X is NR¹⁴, O or S. In another aspect X isNR¹⁴. In yet another aspect X is NH.

In one aspect of the invention m is 1, 2 or 3. In another aspect m is 0,1 or 2. In another aspect m is 1. In a further aspect m is 2.

In one aspect of the invention Z is —NR¹R² or a 4- to 7-memberedsaturated ring linked via a carbon atom, containing a nitrogen atom,which ring is substituted on carbon or nitrogen by phosphonooxy orC₁₋₄alkyl substituted by phosponooxy. In another aspect Z is —NR¹R².

In one aspect of the invention R¹ is C₁₋₅alkyl substituted byphosphonooxy. In another aspect R¹ is C₁₋₅alkyl substituted byphosphonooxy and further substituted by 1 or 2 halo. In a further aspectR¹ is 2-phosphonooxyethyl, 2-phosphonooxy-1,1-dimethylethyl,2-phosphonooxypropyl, 3-phosphonooxy-1,1-dimethylpropyl,3-phosphonooxypropyl and 4-phosphonooxybutyl. In yet another aspect R¹is 2-phosphonooxyethyl

In one aspect of the invention R² is a group selected from hydrogen andC₁₋₄alkyl which C₁₋₄alkyl is optionally substituted by halo orC₁₋₄alkoxy, or R² is a group selected from C₃₋₆cycloalkyl orC₃₋₆cycloalkylC₁₋₄alkyl. In another aspect R² is hydrogen, 2-propynyl,methyl, ethyl, butyl, cyclopropyl, where the latter four groups areoptionally substituted by fluoro, chloro, methoxy and ethoxy. In anotheraspect of the invention R² is hydrogen, 2-propynyl, methyl, ethyl,isobutyl, cyclopropyl, 2-fluoroethyl or 2-methoxyethyl. In anotheraspect of the invention R² is hydrogen, methyl, ethyl, cyclopropyl,2-fluoroethyl or 2-methoxyethyl. In a further aspect R² is hydrogen,methyl or ethyl. In a further aspect R² is hydrogen.

In one aspect of the invention R¹ and R² together with the nitrogen towhich they are attached form a saturated 5- to 6-membered ringoptionally containing a further nitrogen atom wherein the ring issubstituted on carbon on nitrogen by a group selected from phosphonooxy,and C₁₋₄alkyl which C₁₋₄alkyl is substituted by phosphonooxy or —NR⁸R⁹and where the ring is optionally further substituted on carbon ornitrogen, by 1 or 2 C₁₋₄alkyl groups. In another aspect of the inventionR¹ and R² together with the nitrogen to which they are attached form apiperidine, pyrrolidine or piperazine ring which is substituted by agroup selected from phosphonooxy, phosphonooxymethyl,2-phosphonooxyethyl and N-ethyl-N-(2-phosphonooxyethyl)aminomethyl andN-(2-phosphonooxyethyl)aminomethyl and where the ring is optionallyfurther substituted by 1 or 2 methyl. In a further aspect of theinvention R¹ and R² together with the nitrogen to which they areattached form 4-(phosphonooxymethyl)piperidinyl,2-(phosphonooxymethyl)pyrrolidinyl, 4-(2-phosphonooxyethyl)piperazinyl,3-(phosphonooxy)pyrrolidinyl, 3-(phosphonooxy)piperidinyl,2-[N-ethyl-N-(2-phosphonooxyethyl)aminomethyl]pyrrolidinyl,4-(phosphonooxy)piperidinyl,2-[N-(2-phosphonooxyethyl)aminomethyl]pyrrolidinyl,4-(2-phosphonooxyethyl)piperidinyl, 2-(2-phosphonooxyethyl)pyrrolidinyland 2-(2-phosphonooxyethyl)piperidinyl.

In one aspect of the invention R³ is C₁₋₄alkoxy or hydrogen. In anotheraspect R³ is methoxy. In another aspect R³ is hydrogen.

In one aspect R⁴ is phenyl optionally substituted by 1 or 2 of fluoro orchloro. In another aspect R⁴ is 3-fluorophenyl, 3-chlorophenyl,3,5-difluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl,2,3-difluorophenyl, 2,4-difluorophenyl and 2,5-difluorophenyl. Inanother aspect R⁴ is 3-fluorophenyl. In another aspect R⁴ is3-chlorophenyl. In another aspect R⁴ is 3,5-difluorophenyl. In anotheraspect R⁴ is 3,4-difluorophenyl. In another aspect R⁴ is 2-fluorophenyl.In another aspect R⁴ is 2,3-difluorophenyl. In another aspect R⁴ is2,4-difluorophenyl. In another aspect R⁴ is 2,5-difluorophenyl.

In one aspect R⁵ is hydrogen or methyl.

In one aspect of the invention R⁶ is hydrogen, fluoro, chloro or methyl.In another aspect R⁶ is hydrogen.

In one aspect of the invention R⁷ is hydrogen, fluoro, chloro or methyl.In another aspect R⁷ is hydrogen.

In one aspect R⁸ is 2-phosphonooxyethyl.

In one aspect of the invention R⁹ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹⁰ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹¹ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹² is hydrogen or methyl.

In one aspect of the invention R¹³ is hydrogen or methyl.

In one aspect of the invention R¹⁴ is hydrogen or methyl.

A preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a), (b), (c), (d), (e) or (f) as defined    above;-   X is NH;-   m is 1, 2 or 3;-   Z is —NR¹R²;-   R¹ is C₁₋₅alkyl substituted by phosphonooxy;-   R² is hydrogen, 2-propynyl, methyl, ethyl, butyl, cyclopropyl, where    the latter four groups are optionally substituted by fluoro, chloro,    methoxy and ethoxy;-   R³ is C₁₋₄alkoxy or hydrogen;-   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above;-   X is NH;-   m is 0, 1 or 2;-   Z is —NR¹R² or a 4- to 7-membered saturated ring linked via a carbon    atom, containing a nitrogen atom, which ring is substituted on    carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted by    phosponooxy;-   R¹ is C₁₋₅alkyl substituted by phosphonooxy;-   R² is a group selected from hydrogen and C₁₋₄alkyl which C₁₋₄alkyl    is optionally substituted by halo or C₁₋₄alkoxy, or R² is a group    selected from C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₄alkyl;-   R³ is C₁₋₄alkoxy or hydrogen;-   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above;-   X is NH;-   m is 0, 1 or 2;-   Z is —NR¹R²;-   R¹ is C₁₋₅alkyl substituted by phosphonooxy;-   R² is hydrogen, 2-propynyl, methyl, ethyl, butyl, cyclopropyl, where    the latter four groups are optionally substituted by fluoro, chloro,    methoxy and ethoxy;-   R³ is methoxy;-   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above;-   X is NH;-   m is 0, 1 or 2;-   Z is —NR¹R² or a 4- to 7-membered saturated ring linked via a carbon    atom, containing a nitrogen atom, which ring is substituted on    carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted by    phosponooxy;-   R¹ is C₁₋₅alkyl substituted by phosphonooxy;-   R² is hydrogen, 2-propynyl, methyl, ethyl, butyl, cyclopropyl, where    the latter four groups are optionally substituted by fluoro, chloro,    methoxy and ethoxy;-   R³ is hydrogen;-   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a), (b), (c), (d), (e) or (f) as defined    above;-   X is NH;-   m is 1, 2 or 3;-   Z is —NR¹R²;-   R¹ and R² together with the nitrogen to which they are attached form    a saturated 5- to 6-membered ring optionally containing a further    nitrogen atom wherein the ring is substituted on carbon or nitrogen,    by a group selected from phosphonooxy, and C₁₋₄alkyl which C₁₋₄alkyl    is substituted by phosphonooxy or —NR⁸R⁹ and where the ring is    optionally further substituted on carbon on nitrogen, by 1 or 2    C₁₋₄alkyl groups;-   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   R⁸ is 2-phosphonooxyethyl; and-   R⁹ is hydrogen, methyl or ethyl;-   or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above;-   X is NH;-   m is 1, 2 or 3;-   Z is —NR¹R² or a 4- to 7-membered saturated ring linked via a carbon    atom, containing a nitrogen atom, which ring is substituted on    carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted by    phosponooxy;-   R¹ and R² together with the nitrogen to which they are attached form    a saturated 5- to 6-membered ring optionally containing a further    nitrogen atom wherein the ring is substituted on carbon or nitrogen,    by a group selected from phosphonooxy, and C₁₋₄alkyl which C₁₋₄alkyl    is substituted by phosphonooxy or —NR⁸R⁹ and where the ring is    optionally further substituted on carbon or nitrogen, by 1 or 2    C₁₋₄alkyl groups;-   R³ is C₁₋₄alkoxy or hydrogen;-   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   R⁸ is 2-phosphonooxyethyl; and-   R⁹ is hydrogen, methyl or ethyl;-   or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above;-   X is NH;-   m is 1, 2 or 3;-   Z is —NR¹R² or a 4- to 7-membered saturated ring linked via a carbon    atom, containing a nitrogen atom, which ring is substituted on    carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted by    phosponooxy;-   R¹ and R² together with the nitrogen to which they are attached form    a piperidine, pyrrolidine or piperazine ring which is substituted by    a group selected from phosphonooxy, phosphonooxymethyl,    2-phosphonooxyethyl and N-ethyl-N-(2-phosphonooxyethyl)aminomethyl    and N-(2-phosphonooxyethyl)aminomethyl and where the ring is    optionally further substituted by 1 or 2 methyl;-   R³ is methoxy;-   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   R⁵ is 2-phosphonooxyethyl; and-   R⁹ is hydrogen, methyl or ethyl;-   or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above;-   X is NH;-   m is 1, 2 or 3;-   Z is —NR¹R² or a 4- to 7-membered saturated ring linked via a carbon    atom, containing a nitrogen atom, which ring is substituted on    carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted by    phosponooxy;-   R¹ and R² together with the nitrogen to which they are attached form    a piperidine, pyrrolidine or piperazine ring which is substituted by    a group selected from phosphonooxy, phosphonooxymethyl,    2-phosphonooxyethyl and N-ethyl-N-(2-phosphonooxyethyl)aminomethyl    and N-(2-phosphonooxyethyl)aminomethyl and where the ring is    optionally further substituted by 1 or 2 methyl;-   R³ is hydrogen;-   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   R⁸ is 2-phosphonooxyethyl; and-   R⁹ is hydrogen, methyl or ethyl;-   or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, a preferred compound of theinvention is any one selected from:

-   (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-yl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-3-yl    dihydrogen phosphate;-   2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl    dihydrogen phosphate;-   2-((((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   3-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)propyl    dihydrogen phosphate;-   2-((2-fluoroethyl)(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethyl    dihydrogen phosphate;-   2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   (1R)-2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-1-methylethyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyl    dihydrogen phosphate;-   (1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(ethyl(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbutyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl    dihydrogen phosphate;-   2-{cyclopropyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl    dihydrogen phosphate;-   (1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(4-(2-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)ethyl    dihydrogen phosphate;    2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   4-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)butyl    dihydrogen phosphate;-   2-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)ethyl    dihydrogen phosphate;-   (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate; and-   2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

A more preferred compound of the invention is any one selected from:

-   (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-yl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-3-yl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl    dihydrogen phosphate;-   2-((((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyl    dihydrogen phosphate;-   (1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   (1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(4-(2-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate; and-   2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

Another more preferred compound of the invention is any one selectedfrom:

-   2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   3-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)propyl    dihydrogen phosphate;-   2-((2-fluoroethyl)(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   (1R)-2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-1-methylethyl    dihydrogen phosphate;-   2-(ethyl(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    dihydrogen phosphate;-   3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbutyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    dihydrogen phosphate;-   2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl    dihydrogen phosphate;-   2-{cyclopropyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl    dihydrogen phosphate;-   4-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)butyl    dihydrogen phosphate; and-   2-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

A further more preferred compound of the invention is any one selectedfrom:

-   (1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(ethyl(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate; and-   2-(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

Yet another more preferred compound of the invention is any one selectedfrom:

-   (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-yl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-3-yl    dihydrogen phosphate;-   2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl    dihydrogen phosphate;-   2-((((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   3-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)propyl    dihydrogen phosphate;-   2-((2-fluoroethyl)(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethyl    dihydrogen phosphate;-   2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    dihydrogen phosphate;-   2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl    dihydrogen phosphate;-   2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   4-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)butyl    dihydrogen phosphate;-   2-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)ethyl    dihydrogen phosphate;-   (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate; and-   2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

Yet a further more preferred compound of the invention is any oneselected from:

-   ((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbutyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   2-{cyclopropyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl    dihydrogen phosphate;-   (1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate; and-   2-(4-(2-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

Another more preferred compound of the invention is:

-   ((2S)-1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate; or-   2-(1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

A further more preferred compound is any one selected from:

-   ((2R)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate; and-   2-((3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

Another more preferred compound is any one selected from:

-   ((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate; and-   1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

Yet a further more preferred compound of the invention is any oneselected from:

-   2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate; and-   (1R)-2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-1-methylethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

Another preferred compound is:

-   ((2R)-1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate; or-   2-(1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

An especially preferred compound is any one selected from:

-   ((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethyl    dihydrogen phosphate;-   2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   ((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    dihydrogen phosphate;-   1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyl    dihydrogen phosphate;-   2-(4-(3-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    dihydrogen phosphate;-   3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbutyl    dihydrogen phosphate;-   2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    dihydrogen phosphate;-   (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    dihydrogen phosphate; and-   2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl    dihydrogen phosphate;-   or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, which process comprises converting a compoundof formula (II) into a compound of formula (I) by phosphorylation of anappropriate hydroxy group:

where A, X, m, R³, R⁴, R⁵, R⁶, R⁷ and R⁹ are as defined for formula (I);Z′is a group selected from —NR^(1′)R^(2′), hydroxy, C₃₋₆cycloalkyl whichC₃₋₆cycloalkyl is substituted by hydroxy or C₁₋₄alkyl substituted byhydroxy, and a 4- to 7-membered ring linked via a carbon atom,containing a nitrogen atom and optionally containing a further nitrogenatom which ring may be saturated, unsaturated or partially saturated,wherein the ring is substituted on carbon or nitrogen by hydroxy orC₁₋₄alkyl substituted by hydroxy, and wherein the ring is optionallyfurther substituted by 1, 2 or 3 halo or C₁₋₄alkyl groups; and R^(1′) is—COR^(8′), —CONR^(8′)R⁹ or C₁₋₆alkyl which C₁₋₆alkyl is substituted byhydroxy and optionally further substituted on carbon or nitrogen by 1 or2 halo or methoxy groups; R^(2′) is a group selected from hydrogen,—COR¹⁰, —CONR¹⁰R¹¹ and C₁₋₆alkyl which C₁₋₆alkyl is optionallysubstituted by 1, 2, or 3 halo or C₁₋₄alkoxy groups or —S(O)_(p)R¹¹(where p is 0, 1 or 2) or hydroxy, or R² is a group selected fromC₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl; orR^(1′) and R^(2′) together with the nitrogen to which they are attachedform a 4- to 7-membered ring optionally containing a further nitrogenatom which may be saturated, unsaturated or partially saturated, whereinthe ring is substituted on carbon or nitrogen by a group selected fromhydroxy and C₁₋₄alkyl substituted by hydroxy or —NR^(8′)R⁹ and where thering is optionally further substituted on carbon or nitrogen by 1, 2 or3 halo or C₁₋₄alkyl groups; and where R^(8′) is C₁₋₄alkyl substituted byhydroxy and optionally further substituted by 1 or 2 halo or methoxygroups:

-   and thereafter if necessary:-   i) converting a compound of the formula (I) into another compound of    the formula (I); and/or-   ii) removing any protecting groups; and/or-   iii) forming a pharmaceutically acceptable salt thereof.

Phosphorylation may be suitably performed by treatment with 1-Htetrazole (or a suitable replacement such as S-ethyl tetrazole orpyridinium hydrochloride) and di-tert-butyldiethylphosphoramidite ordibenzyldiethylphosphoramidite at 5 to 35° C. under an inert atmospherefor 30 minutes to 4 hours followed by treatment with an oxidizing agentsuch as meta-chloroperbenzoic acid (mCPBA) or 30% aqueous hydrogenperoxide at −10 to 25° C. for 2 to 18 hour. Deprotection of thetert-butyl groups to yield the phosphate group is required as a finalstep with these reagents and may be readily achieved by treatment with4.0 N hydrochloric acid in 1,4-dioxane at 10 to 35° C. for 12 to 18hours.

This process may further comprise a method for the preparation of acompound of formula (II) where Z is —NR^(1′)R^(2′) which methodcomprises the reaction of a compound of formula (III) where L is aleaving group such as halo (e.g. chloro):

with an amine of formula (IV):

Suitable reaction conditions for this method include heating a compoundof formula (III) with an excess of amine of formula (IV) in an inertsolvent such as dimethylacetamide, with or without the addition of asuitable catalyst (such as tetra-n-butylammoniuim iodide or potassiumiodide) at a temperature of 50 to 100° C. for 12 to 72 hours. In analternative procedure, the leaving group L in formula (III) may be acarboxaldehyde and the reaction with amine (IV) may be carried out underreductive conditions using a reducing agent such as sodiumcyanoborohydride.

The amines of formula (IV) are known in the art or may be prepared bythe skilled person using methods known in the art.

The process may further comprise a method for the preparation of acompound of formula (III) where X is NR¹⁴, O or S, which methodcomprises the reaction of a compound of formula (V) where R′ and R″ arealkyl groups such as methyl and ethyl and L is as defined in relation toformula (III):

with a compound of formula (VI) where R may be either hydrogen or agroup such as tert-butoxycarbonyl (Boc) or trityl:

Such a reaction can be achieved under a range of conditions described inthe literature, such as heating a compound of formula (V) with acompound of formula (VI) in a solvent such as acetic acid at atemperature of 100 to 130° C. for 2 to 18 hours.

Alternatively, the process may further comprise a method for thepreparation of a compound of formula (III) where X is NR¹⁴, O or S,which method comprises the reaction of a compound of formula (VII) whereR* is a leaving group such as halo (e.g. chloro):

with a compound of formula (VI) where R is either hydrogen ortert-butoxycarbonyl (Boc) or trityl. Such a reaction can be achievedunder a range of conditions described in the literature, such as heatinga compound of formula (VII) with a compound of formula (VI) in a solventsuch as isopropanol or dimethylacetamide, in the presence of an acidcatalyst such as hydrochloric acid, at a temperature of 80 to 100° C.for 2 to 6 hours. Alternatively the reaction may be effected using abase such as sodium hydride; carrying out the reaction in an inertsolvent such as dimethylformamide at a temperature of 50 to 80° C. for 2to 6 hours.

Compounds of formula (V) can be prepared from a compound of formula(VIII) where P is a hydroxy protecting group such as benzyl:

by reaction with a compound of formula (IX) where L′ is a leaving groupsuch as halo (e.g. bromo) and L is as defined in relation to formula(III):

Such a reaction can be achieved (after removal of the protecting groupusing a method selected from those already described in the literature)under a range of conditions described in the literature such as heatinga compound of formula (VIII) with a compound of formula (IX) in thepresence of a catalyst such as caesium carbonate in a solvent such asacetonitrile at a temperature of 80 to 100° C. for 1 to 4 hours.

A method for the preparation of a compound of formula (VIII) comprisesthe reaction of a compound of formula (X) where P is as defined inrelation for formula (VIII):

with an appropriate acetal such as N,N-dimethylformamide dimethylacetal. The reaction is suitably effected in an organic solvent such astoluene or benzene, at elevated temperature, conveniently at the refluxtemperature of the solvent.

Compounds of formula (X) are either known compounds or they can beprepared by the skilled person using conventional methods. Inparticular, compounds of formula (X) may be prepared reduction of thecorresponding nitro compound of formula (XI) where P is as described inrelation to formula (VIII):

Suitable reaction conditions are illustrated herein.

Compounds of formula (XI) may be obtained by nitration of a compound offormula (XII) where P is as defined in relation to formula (VIII)

for example, using nitric acid as the nitrating agent. Again, suitablereaction conditions are illustrated herein.

The nitrile of formula (XII) may be derived by reaction of thecorresponding aldehyde of formula (XIII) with hydroxylamine asillustrated herein.

The process may further comprise a method for the preparation of acompound according to formula (VII) which method comprises the reactionof a compound of formula (XIV)

where L* is a hydroxy group, with a suitable chlorinating agent such asthionyl chloride, phoshoryl chloride or phoshorus pentachloride. Again,suitable reaction conditions are illustrated herein.

Compounds of formula (XI) are either known compounds or they can beprepared by the skilled person using conventional methods. Inparticular, compounds of formula (XIV) may be prepared by reaction of acompound of formula (XV) where L″ is a leaving group such as halo(fluoro)

with a compound of formula (XVI) where L* is a hydroxy group:

Suitable reaction conditions are illustrated herein.

Compounds of formula (XV) are either known compounds or they can beprepared by the skilled person using conventional methods. Inparticular, compounds of formula (XV) may be prepared by reaction of acompound of formula (XVII) (where L″ is a leaving group such as halo(fluoro) and L′″ is an alkoxy or hydroxy group) by reaction with neatformamide at a temperature of 140 to 200° C. for 3 to 6 hours.

Suitable reaction conditions are illustrated herein.

Compounds of formula (XVII) are either known compounds or they can beprepared by the skilled person using conventional methods. Inparticular, compounds of formula (XVII) may be prepared by reduction ofa compound of formula (XVIII) (where L″ is a leaving group such as halo(fluoro) and L′″ is an alkoxy or hydroxy group) using a reducing agentsuch as sodium dithionite in a water:dichloromethane solvent system atambient temperature for 1 to 3 hours.

Compounds of formula (XVIII) may be obtained by nitration of a compoundof formula (XIX) where L″ and L′″ are as defined in relation to formula(XVIII)

for example, using nitric acid as the nitrating agent. Again, suitablereaction conditions are illustrated herein.

The process may further comprise a method for the preparation of acompound according to formula (VI) where X is NR¹⁴, O or S, which methodcomprises the reaction of a compound of formula (XX), where P is asuitable protecting group:

with an amine of formula HNR⁴R⁵ in the presence of a coupling reagent(such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) and diisopropylethylamine in a solvent (such asdimethylacetamide) under inert and anhydrous conditions.

A compound of formula (XX) where X is NH may be prepared from a compoundof formula (XXI):

with a compound of formula (XXII) where L is an appropriate leavinggroup:

Suitable reagent and reaction conditions for this reaction include theuse of di(tert-butyldicarbonate and triethylamine in tetrahydrofuran at0° C. under a nitrogen atmosphere.

A compound of formula (III) may also be prepared (followingdeprotection) from a compound of formula (XX) by reacting it with acompound of formula (V) under a range of conditions described in theliterature, such as heating the reaction mixture in a solvent such asacetic acid at a temperature of 100 to 130° C. for 2 to 18 hours. Theproduct, a compound of formula (XXIII):

may then be reacted with an amine of formula HNR⁴R⁵ in the presence of acoupling agent (such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) and diisopropylethylamine in a solvent (such asdimethylacetamide) under inert and anhydrous conditions.

Further a compound of formula (XXII) may also be prepared by reacting adeprotected compound of formula (XX) with a compound of formula (VII)under a range of conditions described in the literature, such as heatingthe reaction mixture in a solvent such as isopropanol ordimethylacetamide, in the presence of an acid catalyst such ashydrochloric acid, at a temperature of 80 to 100° C. for 2 to 6 hours.Alternatively the reaction may be effected using a base such as sodiumhydride; carrying out the reaction in an inert solvent such asdimethylformamide at a temperature of 50 to 80° C. for 2 to 6 hours.

Compounds of formula (XXI) which comprise a heteraromatic ring are madeaccording to the literature. However for illustrative purpose, when A isa thiazole ring, a compound of formula (XXI) may be prepared accordingto the following scheme:

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogen group. Particular examplesof modifications include the reduction of a nitro group to an aminogroup by for example, catalytic hydrogenation with a nickel catalyst ortreatment with iron in the presence of hydrochloric acid with heating;oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt thereof, as defined herein inassociation with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal track, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, soya bean oil, coconut oil,or preferably olive oil, or any other acceptable vehicle

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible or lyophilised powders and granules suitable for preparationof an aqueous suspension or solution by the addition of water generallycontain the active ingredient together with a dispersing or wettingagent, suspending agent and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose already mentioned above. Additional excipients such as sweetening,flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, solutions, emulsions orparticular systems, which may be formulated according to knownprocedures using one or more of the appropriate dispersing or wettingagents and suspending agents, which have been mentioned above. A sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in polyethylene glycol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedure well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less preferably 5 μm or less and more preferablybetween 5 μm and 1 μm, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

Therefore in a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,for use in therapy. Further provided is a compound of formula (I), or apharmaceutically acceptable salt thereof, for use as a medicament. Acompound of formula (I), or a pharmaceutically acceptable salt thereof,is also provided for use in the treatment of a disease where theinhibition of one or more Aurora kinase is beneficial. In particular itis envisaged that inhibition of Aurora-A kinase and/or Aurora-B kinasemay be beneficial. Preferably inhibition of Aurora-B kinase isbeneficial. A compound of formula (I), or a pharmaceutically acceptablesalt thereof, has further use in the treatment of hyperproliferativediseases such as cancer and in particular colorectal, breast, lung,prostate, pancreatic or bladder and renal cancer or leukemias orlymphomas.

Additionally a compound of formula (I), or a pharmaceutically acceptablesalt thereof is provided for use in a method of treatment of awarm-blooded animal such as man by therapy. According to this aspect,there is provided a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in the method of treating a humansuffering from a disease in which the inhibition of one or more Aurorakinases is beneficial, comprising the steps of administering to a personin need thereof a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof. In particularit is envisaged that inhibition of Aurora-A kinase and/or Aurora-Bkinase may be beneficial. Preferably inhibition of Aurora-B kinase isbeneficial. Further provided is a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the method oftreating a human suffering from a hyperproliferative disease such ascancer and in particular particular colorectal, breast, lung, prostate,pancreatic or bladder and renal cancer or leukemias or lymphomas,comprising the steps of administering to a person in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof,in the preparation of a medicament for the treatment of a disease wherethe inhibition of one or more Aurora kinase is beneficial. In particularit is envisaged that inhibition of Aurora-A kinase and/or Aurora-Bkinase may be beneficial. Preferably inhibition of Aurora-B kinase isbeneficial. In another aspect of the invention, there is provided theuse of a compound of formula (I) or a pharmaceutically acceptable saltthereof, in the preparation of a medicament for the treatment ofhyperproliferative diseases such as cancer and in particular colorectal,breast, lung, prostate, pancreatic or bladder and renal cancer orleukemias or lymphomas.

For the above mentioned therapeutic uses the dose administered will varywith the compound employed, the mode of administration, the treatmentdesired, the disorder indicated and the age and sex of the animal orpatient. The size of the dose would thus be calculated according to wellknown principles of medicine.

In using a compound of formula (I) for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.05 mg/kg to 50 mg/kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.05 mg/kgto 25 mg/kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.05mg/kg to 25 mg/kg body weight will be used.

The treatment defined herein may be applied as a sole therapy or mayinvolve, in addition to the compound of the invention, conventionalsurgery or radiotherapy or chemotherapy. Such chemotherapy may includeone or more of the following categories of anti-tumour agents:

-   (i) antiproliferative/antineoplastic drugs and combinations thereof,    as used in medical oncology, such as alkylating agents (for example    cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,    melphalan, chlorambucil, busulphan and nitrosoureas);    antimetabolites (for example antifolates such as fluoropyrimidines    like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside and hydroxyurea; antitumour antibiotics (for example    anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,    epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);    antimitotic agents (for example vinca alkaloids like vincristine,    vinblastine, vindesine and vinorelbine and taxoids like taxol and    taxotere); and topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan and camptothecin);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iii) Agents which inhibit cancer cell invasion (for example    metalloproteinase inhibitors like marimastat and inhibitors of    urokinase plasminogen activator receptor function);-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies (for example the anti-erbb2 antibody trastuzumab    [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl    transferase inhibitors, tyrosine kinase inhibitors and    serine-threonine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors such as    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, AZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents such as those which inhibit the effects of    vascular endothelial growth factor, (for example the anti-vascular    endothelial cell growth factor antibody bevacizumab [Avastin™],    compounds such as those disclosed in International Patent    Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)    and compounds that work by other mechanisms (for example linomide,    inhibitors of integrin αvβ3 function and angiostatin);-   (vi) vascular damaging agents such as Combretastatin A4 and    compounds disclosed in International Patent Applications WO    99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and    WO02/08213;-   (vii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (viii) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such    as those using cytosine deaminase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (ix) immunotherapy approaches, including for example ex vivo and in    vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-transfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies.    In addition a compound of the invention may be used in combination    with one or more cell cycle inhibitors. In particular with cell    cycle inhibitors which inhibit bub1, bubR1 or CDK. Such conjoint    treatment may be achieved by way of the simultaneous, sequential or    separate dosing of the individual components of the treatment. Such    combination products employ the compounds of this invention within    the dosage range described herein and the other pharmaceutically    active agent within its approved dosage range.

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of cell cycle activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

The compounds of the invention inhibit the serine-threonine kinaseactivity of the Aurora kinases, in particular Aurora-A and/or Aurora-Band thus inhibit the cell cycle and cell proliferation. These propertiesmay be assessed for example, using one or more of the procedures set outbelow. Whilst not wishing to be bound by theoretical constraints, it isbelieved that the compounds of formula (I) described herein may act asprodrugs. In procedures (c) and (d) set out below it is believed that aphosphonooxy group present in the compound of formula (I) is cleaved insitu to yield a hydroxy group and that such cleavage is necessary foractivity is these assays.

(a) In Vitro Aurora-A Kinase Inhibition Test

This assay determines the ability of a test compound to inhibitserine-threonine kinase activity. DNA encoding Aurora-A may be obtainedby total gene synthesis or by cloning. This DNA may then be expressed ina suitable expression system to obtain polypeptide with serine-threoninekinase activity. In the case of Aurora-A, the coding sequence wasisolated from cDNA by polymerase chain reaction (PCR) and cloned intothe BamH1 and Not1 restriction endonuclease sites of the baculovirusexpression vector pFastBac HTc (GibcoBRL/Life technologies). The 5′ PCRprimer contained a recognition sequence for the restriction endonucleaseBamH1 5′ to the Aurora-A coding sequence. This allowed the insertion ofthe Aurora-A gene in frame with the 6 histidine residues, spacer regionand rTEV protease cleavage site encoded by the pFastBac HTc vector. The3′ PCR primer replaced the Aurora-A stop codon with additional codingsequence followed by a stop codon and a recognition sequence for therestriction endonuclease Not1. This additional coding sequence (5′ TACCCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3′) encoded for the polypeptidesequence YPYDVPDYAS. This sequence, derived from the influenzahemagglutin protein, is frequently used as a tag epitope sequence thatcan be identified using specific monoclonal antibodies. The recombinantpFastBac vector therefore encoded for an N-terminally 6 his tagged, Cterminally influenza hemagglutin epitope tagged Aurora-A protein.Details of the methods for the assembly of recombinant DNA molecules canbe found in standard texts, for example Sambrook et al. 1989, MolecularCloning—A Laboratory Manual, 2^(nd) Edition, Cold Spring HarborLaboratory press and Ausubel et al. 1999, Current Protocols in MolecularBiology, John Wiley and Sons Inc.

Production of recombinant virus can be performed followingmanufacturer's protocol from GibcoBRL. Briefly, the pFastBac-1 vectorcarrying the Aurora-A gene was transformed into E. coli DH10Bac cellscontaining the baculovirus genome (bacmid DNA) and via a transpositionevent in the cells, a region of the pFastBac vector containinggentamycin resistance gene and the Aurora-A gene including thebaculovirus polyhedrin promoter was transposed directly into the bacmidDNA. By selection on gentamycin, kanamycin, tetracycline and X-gal,resultant white colonies should contain recombinant bacmid DNA encodingAurora-A. Bacmid DNA was extracted from a small scale culture of severalBH10Bac white colonies and transfected into Spodoptera frugiperda Sf21cells grown in TC100 medium (GibcoBRL) containing 10% serum usingCellFECTIN reagent (GibcoBRL) following manufacturer's instructions.Virus particles were harvested by collecting cell culture medium 72 hrspost transfection. 0.5 mls of medium was used to infect 100 mlsuspension culture of Sf21s containing 1×10⁷ cells/ml. Cell culturemedium was harvested 48 hrs post infection and virus titre determinedusing a standard plaque assay procedure. Virus stocks were used toinfect Sf9 and “High 5” cells at a multiplicity of infection (MOI) of 3to ascertain expression of recombinant Aurora-A protein.

For the large scale expression of Aurora-A kinase activity, Sf21 insectcells were grown at 28° C. in TC100 medium supplemented with 10% foetalcalf serum (Viralex) and 0.2% F68 Pluronic (Sigma) on a Wheaton rollerrig at 3 r.p.m. When the cell density reached 1.2×10⁶ cells ml⁻¹ theywere infected with plaque-pure Aurora-A recombinant virus at amultiplicity of infection of 1 and harvested 48 hours later. Allsubsequent purification steps were performed at 4° C. Frozen insect cellpellets containing a total of 2.0×10⁸ cells were thawed and diluted withlysis buffer (25 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulphonic acid]) pH7.4 at 4°C., 100 mM KCl, 25 mM NaF, 1 mM Na₃VO₄, 1 mM PMSF (phenylmethylsulphonylfluoride), 2 mM 2-mercaptoethanol, 2 mM imidazole, 1 μg/ml aprotinin, 1μg/ml pepstatin, 1 μg/ml leupeptin), using 1.0 ml per 3×10⁷ cells. Lysiswas achieved using a dounce homogeniser, following which the lysate wascentrifuged at 41,000 g for 35 minutes. Aspirated supernatant was pumpedonto a 5 mm diameter chromatography column containing 500 μl Ni NTA(nitrilo-tri-acetic acid) agarose (Qiagen, product no. 30250) which hadbeen equilibrated in lysis buffer. A baseline level of UV absorbance forthe eluent was reached after washing the column with 12 ml of lysisbuffer followed by 7 ml of wash buffer (25 mM HEPES pH7.4 at 4° C., 100mM KCl, 20 mM imidazole, 2 mM 2-mercaptoethanol). Bound Aurora-A proteinwas eluted from the column using elution buffer (25 mM HEPES pH7.4 at 4°C., 100 mM KCl, 400 mM imidazole, 2 mM 2-mercaptoethanol). An elutionfraction (2.5 ml) corresponding to the peak in UV absorbance wascollected. The elution fraction, containing active Aurora-A kinase, wasdialysed exhaustively against dialysis buffer (25 mM HEPES pH7.4 at 4°C., 45% glycerol (v/v), 100 mM KCl, 0.25% Nonidet P40 (v/v), 1 mMdithiothreitol).

Each new batch of Aurora-A enzyme was titrated in the assay by dilutionwith enzyme diluent (25 mM Tris-HCl pH7.5, 12.5 mM KCl, 0.6 mM DTT). Fora typical batch, stock enzyme is diluted 1 in 666 with enzyme diluentand 20 μl of dilute enzyme is used for each assay well. Test compounds(at 10 mM in dimethylsulphoxide (DMSO) were diluted with water and 10 μlof diluted compound was transferred to wells in the assay plates.“Total” and “blank” control wells contained 2.5% DMSO instead ofcompound. Twenty microlitres of freshly diluted enzyme was added to allwells, apart from “blank” wells. Twenty microlitres of enzyme diluentwas added to “blank” wells. Twenty microlitres of reaction mix (25 mMTris-HCl, 78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM MnCl₂,6.25 mM ATP, 7.5 μM peptide substrate[biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) containing 0.2 μCi [γ³³P]ATP(Amersham Pharmacia, specific activity ≧2500 Ci/mmol) was then added toall test wells to start the reaction. The plates were incubated at roomtemperature for 60 minutes. To stop the reaction 100 μl 20% v/vorthophosphoric acid was added to all wells. The peptide substrate wascaptured on positively-charged nitrocellulose P30 filtermat (Whatman)using a 96-well plate harvester (TomTek) and then assayed forincorporation of ³³P with a Beta plate counter. “Blank” (no enzyme) and“total” (no compound) control values were used to determine the dilutionrange of test compound which gave 50% inhibition of enzyme activity.

In this test, the compounds of the invention give 50% inhibition ofenzyme activity at concentrations of 0.3 nM to 1000 nM and in particularcompound 2 in Table 1 gave 50% inhibition of enzyme activity at aconcentration of 10.2 nM.

(b) In Vitro Aurora-B Kinase Inhibition Test

This assay determines the ability of a test compound to inhibitserine-threonine kinase activity. DNA encoding Aurora-B may be obtainedby total gene synthesis or by cloning. This DNA may then be expressed ina suitable expression system to obtain polypeptide with serine-threoninekinase activity. In the case of Aurora-B, the coding sequence wasisolated from cDNA by polymerase chain reaction (PCR) and cloned intothe pFastBac system in a manner similar to that described above forAurora-A (i.e. to direct expression of a 6-histidine tagged Aurora-Bprotein).

For the large scale expression of Aurora-B kinase activity, Sf21 insectcells were grown at 28° C. in TC100 medium supplemented with 10% foetalcalf serum (Viralex) and 0.2% F68 Pluronic (Sigma) on a Wheaton rollerrig at 3 r.p.m. When the cell density reached 1.2×10⁶ cells ml⁻¹ theywere infected with plaque-pure Aurora-B recombinant virus at amultiplicity of infection of 1 and harvested 48 hours later. Allsubsequent purification steps were performed at 4° C. Frozen insect cellpellets containing a total of 2.0×10⁸ cells were thawed and diluted withlysis buffer (50 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulphonic acid]) pH7.5 at 4°C., 1 mM Na₃VO₄, 1 mM PMSF (phenylmethylsulphonyl fluoride), 1 mMdithiothreitol, 1 μg/ml aprotinin, 1 μg/ml pepstatin, 1 μg/mlleupeptin), using 1.0 ml per 2×10⁷ cells. Lysis was achieved using asonication homogeniser, following which the lysate was centrifuged at41,000 g for 35 minutes. Aspirated supernatant was pumped onto a 5 mmdiameter chromatography column containing 1.0 ml CM sepharose Fast Flow(Amersham Pharmacia Biotech) which had been equilibrated in lysisbuffer. A baseline level of UV absorbance for the eluent was reachedafter washing the column with 12 ml of lysis buffer followed by 7 ml ofwash buffer (50 mM HEPES pH7.4 at 4° C., 1 mM dithiothreitol). BoundAurora-B B protein was eluted from the column using a gradient ofelution buffer (50 mM HEPES pH7.4 at 4° C., 0.6 M NaCl, 1 mMdithiothreitol, running from 0% elution buffer to 100% elution bufferover 15 minutes at a flowrate of 0.5 ml/min). Elution fractions (1.0 ml)corresponding to the peak in UV absorbance was collected. Elutionfractions were dialysed exhaustively against dialysis buffer (25 mMHEPES pH7.4 at 4° C., 45% glycerol (v/v), 100 mM KCl, 0.05% (v/v) IGEPALCA630 (Sigma Aldrich), 1 mM dithiothreitol). Dialysed fractions wereassayed for Aurora-B kinase activity.

Each new batch of Aurora-B enzyme was titrated in the assay by dilutionwith enzyme diluent (25 mM Tris-HCl pH7.5, 12.5 mM KCl, 0.6 mM DTT). Fora typical batch, stock enzyme is diluted 1 in 40 with enzyme diluent and20 μl of dilute enzyme is used for each assay well. Test compounds (at10 mM in dimethylsulphoxide (DMSO) were diluted with water and 10 μl ofdiluted compound was transferred to wells in the assay plates. “Total”and “blank” control wells contained 2.5% DMSO instead of compound.Twenty microlitres of freshly diluted enzyme was added to all wells,apart from “blank” wells. Twenty microlitres of enzyme diluent was addedto “blank” wells. Twenty microlitres of reaction mix (25 mM Tris-HCl,78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM MnCl₂, 37.5 mMATP, 25 μM peptide substrate [biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG])containing 0.2 μCi [γ³³P]ATP (Amersham Pharmacia, specific activity≧2500 Ci/mmol) was then added to all test wells to start the reaction.The plates were incubated at room temperature for 60 minutes. To stopthe reaction 100 μl 20% v/v orthophosphoric acid was added to all wells.The peptide substrate was captured on positively-charged nitrocelluloseP30 filtermat (Whatman) using a 96-well plate harvester (TomTek) andthen assayed for incorporation of ³³P with a Beta plate counter. “Blank”(no enzyme) and “total” (no compound) control values were used todetermine the dilution range of test compound which gave 50% inhibitionof enzyme activity.

In this test, the compounds of the invention give 50% inhibition ofenzyme activity at concentrations of 0.3 nM to 1000 nM and in particularcompound 2 in Table 1 gave 50% inhibition of enzyme activity at aconcentration of 9 nM.

(c) In Vitro Cell Proliferation Assay

This and other assays can be used to determine the ability of a testcompound to inhibit the growth of adherent mammalian cell lines, forexample the human tumour cell line SW620 (ATCC CCL-227). This assaydetermines the ability of at test compound to inhibit the incorporationof the thymidine analogue, 5′-bromo-2′-deoxy-uridine (BrdU) intocellular DNA. SW620 or other adherent cells were typically seeded at1×10⁵ cells per well in L-15 media (GIBCO) plus 5% foetal calf serum, 1%L-glutamine (100 μl/well) in 96 well tissue culture treated 96 wellplates (Costar) and allowed to adhere overnight. The following day thecells were dosed with compound (diluted from 10 mM stock in DMSO usingL-15 (with 5% FCS, 1% L-glutamine). Untreated control wells and wellscontaining a compound known to give 100% inhibition of BrdUincorporation were included on each plate. After 48 hours in thepresence/absence of test compound the ability of the cells toincorporate BrdU over a 2 hour labelling period was determined using aBoehringer (Roche) Cell Proliferation BrdU ELISA kit (cat. No. 1 647229) according to manufacturers directions. Briefly, 15 μl of BrdUlabelling reagent (diluted 1:100 in media—L-15, 5% FCS, 1% L-glutamine)was added to each well and the plate returned to a humidified (+5% CO₂)37° C. incubator for 2 hours. After 2 hours the labelling reagent wasremoved by decanting and tapping the plate on a paper towel. FixDenatsolution (50 μl per well) was added and the plates incubated at roomtemperature for 45 minutes with shaking. The FixDenat solution wasremoved by decanting and tapping the inverted plate on a paper towel.The plate was then washed once with phosphate buffered saline (PBS) and100 μl/well of Anti-BrdU-POD antibody solution (diluted 1:100 inantibody dilution buffer) added. The plate was then incubated at roomtemperature with shaking for 90 minutes. Unbound Anti-BrdU-POD antibodywas removed by decanting and washing the plate 4 times with PBS beforebeing blotted dry. TMB substrate solution was added (100 μl/well) andincubated for approximately 10 minutes at room temperature with shakinguntil a colour change was apparent. The optical density of the wells wasthen determined at 690 nm wavelength using a Titertek Multiscan platereader. The values from compound treated, untreated and 100% inhibitioncontrols were used to determine the dilution range of a test compoundthat gave 50% inhibition of BrdU incorporation. The compounds of theinvention are active at 0.3 nM to 10000 nM in this test and inparticular compound 2 in table 1 was active at 6 nM.

(d) In Vitro Cell Cycle Analysis Assay

This assay determines the ability of a test compound to arrest cells inspecific phases of the cell cycle. Many different mammalian cell linescould be used in this assay and SW620 cells are included here as anexample. SW620 cells were seeded at 7×10⁵ cells per T25 flask (Costar)in 5 ml L-15 (5% FCS, 1% L-glutamine). Flasks were then incubatedovernight in a humidified 37° C. incubator with 5% CO₂. The followingday, 5 μl of L-15 (5% FCS, 1% L-glutamine) carrying the appropriateconcentration of test compound solubilised in DMSO was added to theflask. A no compound control treatments was also included (0.5% DMSO).The cells were then incubated for a defined time (24 hours) withcompound. After this time the media was aspirated from the cells andthey were washed with 5 ml of prewarmed (37° C.) sterile PBSA, thendetached from the flask by brief incubation with trypsin and followed byresuspension in 5 ml of 1% Bovine Serum Albumin (BSA, Sigma-Aldrich Co.)in sterile PBSA. The samples were then centrifuged at 2200 rpm for 10minutes. The supernatant was aspirated to leave 200 μl of the PBS/BSAsolution. The pellet was resuspended in this 200 μl of solution bypipetting 10 times to create a single cell suspension. One ml ofice-cold 80% ethanol was slowly added to each cell suspension and thesamples stored at −20° C. overnight or until required for staining.Cells were pelleted by centrifugation, ethanol aspirated off and pelletsresuspended in 200 μl PBS containing 100 μg/ml RNAse (Sigma Aldrich) and10 μg/ml Propidium Iodide (Sigma Aldrich). Cell suspensions wereincubated at 37° C. for 30 min, a further 200 μl PBS added and samplesstored in the dark at 4° C. overnight.

Each sample was then syringed 10 times using 21-guage needle. Thesamples were then transferred to LPS tubes and DNA content per cellanalysed by Fluorescence activated cell sorting (FACS) using a FACScanflow cytometer (Becton Dickinson). Typically 30,000 events were countedand recorded using CellQuest v1.1 software (Verity Software). Cell cycledistribution of the population was calculated using Modfit software(Verity Software) and expressed as percentage of cells with 2N (G0/G1),2N-4N (S phase) and with 4N (G2/M) DNA content.

The compounds of the invention are active at 0.3 nM to 10000 nM in thistest and in particular compound 2 in table 1 was active at 20 nM.

The invention will now be illustrated in the following non limitingexamples, in which standard techniques known to the skilled chemist andtechniques analogous to those described in these examples may be usedwhere appropriate, and in which, unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work up procedures were carried out after removal of residual solids    such as drying agents by filtration;-   (ii) operations were carried out at ambient temperature, typically    in the range 18-25° C. and in air unless stated, or unless the    skilled person would otherwise operate under an atmosphere of an    inert gas such as argon;-   (iii) column chromatography (by the flash procedure) and medium    pressure liquid chromatography (MPLC) were performed on Merck    Kieselgel silica (Art. 9385) or on Merck Lichroprep RP-18    (Art. 9303) reversed-phase silica, obtained from E. Merck,    Darmstadt, Germany; bond elute chromatography was performed using    Varian Mega Bond Elut cartridges (10 g, order code 1225-6034),    obtained from Varian Sample Preparation Products, California, USA;-   (iv) yields are given for illustration only and are not necessarily    the maximum attainable;-   (v) the structures of the end products of the formula (I) were    generally confirmed by nuclear (generally proton) magnetic resonance    (NMR) and mass spectral techniques; proton magnetic resonance    chemical shift values were measured in deuterated DMSO d₆ (unless    otherwise stated) on the delta scale (ppm downfield from    tetramethylsilane) using a Varian Gemini 2000 spectrometer operating    at a field strength of 300 MHz, or a Bruker DPX300 spectrometer    operating at a field strength of 300 MHz; and peak multiplicities    are shown as follows: s, singlet; d, doublet; dd, double doublet; t,    triplet; q, quartet; qu, quintet; m, multiplet; bs, broad singlet;    mass spectrometry (MS) was performed by electrospray on a VG    platform;-   (vi) robotic synthesis was carried out using a Zymate XP robot, with    solution additions via a Zymate Master Laboratory Station and    stirred via a Stem RS5000 Reacto-Station at 25° C.;-   (vii) work up and purification of reaction mixtures from robotic    synthesis was carried out as follows: evaporations were carried out    in vacuo using a Savant AES 2000; column chromatography was    performed using either an Anachem Sympur MPLC-or Jones Flashmaster    MPLC systems on silica using Varian Mega Bond Elut cartridges; the    structures of the final products were confirmed by LCMS on a    Micromass OpenLynx system using the following and are quoted as    retention time (RT) in minutes:-   Column: 4.6 mm×3 cm Hichrom RPB-   Solvent A: 5% Methanol in Water+0.1% formic acid-   Solvent B: 5% Methanol in Acetonitrile+0.1% formic acid-   Flow rate: 1.4 ml/min-   Run time: 5 minutes with a 4.5 minute gradient from 0-100% B-   Wavelength: 254 nm, bandwidth 10 nm-   Mass detector: Micromass Platform LC-   Injection volume 0.002 ml-   (vii) Analytical LCMS for compounds which had not been prepared by    robotic synthesis was performed on a a Waters Alliance HT system    using the following and are quoted as retention time (RT) in    minutes:-   Column: 2.0 mm×5 cm Phenomenex Max-RP 80A-   Solvent A: Water-   Solvent B: Acetonitrile-   Solvent C: Methanol+1% formic acid-   Flow rate: 1.1 ml/min-   Run time: 5 minutes with a 4.5 minute gradient from 0-95% B+constant    5% solvent C-   Wavelength: 254 nm, bandwidth 10 nm-   Injection volume 0.005 ml-   Mass detector: Micromass ZMD-   (viii) Preparative high performance liquid chromatography (HPLC) was    performed on a Gilson instrument using the following and are quoted    as retention time (RT) in minutes:-   Column: 21 mm×10 cm Hichrom RPB-   Solvent A: Water+0.1% trifluoracetic acid,-   Solvent B: Acetonitrile+0.1% trifluoracetic acid-   Flow rate: 18 ml/min-   Run time: 15 minutes with a 10 minute gradient from 5-100% B-   Wavelength: 254 nm, bandwidth 10 nm-   Injection volume 2.0-4.0 ml-   (ix) intermediates were not generally fully characterised and purity    was assessed by thin layer chromatography (TLC), HPLC, infra-red    (IR), MS or NMR analysis.

Particular examples of compounds of formula (I) are set out in thefollowing tables, in which TABLE 1

N^(o). R^(x) R^(y) R^(z) 1

H 3-fluorophenyl 2

H 3-fluorophenyl 3

H 3-fluorophenyl 4

H 3-fluorophenyl 5

H 3-fluorophenyl 6

H 3-fluorophenyl 7

H 3-fluorophenyl 8

H 3-fluorophenyl 9

H 3-fluorophenyl 10

H 3-fluorophenyl 11

H 3-fluorophenyl 12

H 3-fluorophenyl 13

H 3-fluorophenyl 14

H 3-fluorophenyl 15

H 3-fluorophenyl 16

H 3-fluorophenyl 17

H 3-fluorophenyl 18

H 3-chlorophenyl 19

H 3-chlorophenyl 20

H 3,5-difluorophenyl 21

H 3,5-difluorophenyl 22

H 3,5-difluorophenyl 23

H 3,5-difluorophenyl 24

H 3,4-difluorophenyl 25

H 3,4-difluorophenyl 26

H 3,4-difluorophenyl 27

H 2-fluorophenyl 28

H 2-fluorophenyl 29

H 2-fluorophenyl 30

H 2-fluorophenyl 31

H 2-fluorophenyl 32

H 2,3-difluorophenyl 33

H 2,3-difluorophenyl 34

H 2,3-difluorophenyl 35

H 2,3-difluorophenyl 36

H 2,3-difluorophenyl 37

H 2,3-difluorophenyl 38

H 2,3-difluorophenyl 39

H 2,3-difluorophenyl 40

H 2,3-difluorophenyl 41

H 2,3-difluorophenyl 42

H 2,5-difluorophenyl 43

H 2,5-difluorophenyl 44

H 2,5-difluorophenyl 45

H 2,4-difluorophenyl 46

H 2,4-difluorophenyl 47

H 3-fluorophenyl 48

H 2,3-difluorophenyl

TABLE 2

N^(o). R^(x) R^(y) R^(z) 49

H 2,3-difluorophenyl 50

H 2,3-difluorophenyl 51

H 2,3-difluorophenyl 52

H 3-fluorophenyl 53

H 3-fluorophenyl 54

H 3-fluorophenyl 55

H 3-fluorophenyl

TABLE 3

N^(o). R^(x) R^(y) R^(z) 56

H 3-fluorophenyl

TABLE 4

N^(o). R^(x) R^(y) R^(z) 57

H 3-fluorophenyl

EXAMPLE 1 Preparation of Compound 1 in Table1—(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyldihydrogen phosphate

Di(tert-butyl)(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate (6.64 g, 8.6 mmol), in 1,4-dioxane (250 ml) was treated with4.0 N hydrochloric acid in 1,4-dioxane (15 ml, 60 mmol) at 20° C. for 18hours. The solid product was collected by suction filtration and washedwith i) 1,4-dioxane (100 ml), ii) acetonitrile (100 ml) and iii) diethylether (100 ml), Prolonged drying in vacuo yielded the title compound(6.73 g, 98% yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.95 (s, 1H), 10.60 (br s, 1H), 9.00 (s, 1H), 7.85(s, 1H), 7.65 (m, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.38 (m, 2H), 6.90(m, 1H), 4.30 (m, 2H), 4.03 (s, 2H), 3.95 (s, 3H), 3.70 (m, 2H), 3.55(m, 2H), 3.20 (m, 2H), 2.97 (m, 2H), 2.35 (m, 2H), 1.90 (m, 3H), 1.60(m, 2H):

MS (+ve ESI): 661 (M+H)⁺

MS (−ve ESI): 659 (M−H)⁻.

Di(tert-butyl)(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate used as the starting material was obtained as follows:

-   a) A mixture of 4-benzyloxy-3-methoxybenzaldehyde (157 g, 649 mmol),    sodium acetate (106 g, 1.29 mol), hydroxylamine hydrochloride (90 g,    1.29 mol) and acetic acid (500 ml) was heated at reflux for 21    hours. The solvent was evaporated in vacuo and ice/water (1000 ml)    was added to the residue, forming a sticky solid. The mixture was    neutralised by addition of aqueous sodium hydroxide solution then    extracted with dichloromethane (2×500 ml). The organic solution was    washed with 1.0 N sodium hydroxide (100 ml) and brine (100 ml) and    then dried over magnesium sulphate. Solvent evaporation in vacuo,    followed by trituration of the residue with hexane:ethyl acetate    (3:1) and collection of the solid by suction filtration yielded    4-benzyloxy-3-methoxybenzonitrile (123 g, 80% yield) as a brown    solid:

¹H-NMR (DMSO d₆): 7.38 (m, 7H), 7.19 (m, 1H), 5.18 (s, 2H), 3.80 (s,3H):

MS (−ve ESI): 238 (M−H)⁻.

-   b) Acetic acid (17 ml) was added slowly to nitric acid (40 ml, 440    mmol) at 5° C. Powdered 4-benzyloxy-3-methoxybenzonitrile (10 g, 42    mmol) was added and the mixture warmed to 23° C. over 10 minutes. An    exotherm occurred and the temperature was controlled at <30° C.    using an ice bath. The reaction was stirred at 23° C. for 20 hours    then poured into ice/water (1000 ml). After stirring for two hours    the yellow solid was collected by suction filtration, washed with    water and dried to yield 4-benzyloxy-3-methoxy-6-nitrobenzonitrile    (10.1 g, 85% yield) as a yellow solid:

¹H-NMR (DMSO d₆): 7.95 (s, 1H), 7.70 (s, 1H), 7.40 (m, 5H), 5.30 (s,2H), 3.95 (s, 3H):

MS (−ve ESI): 283 (M−H)⁻.

-   c) A mixture of 4-benzyloxy-3-methoxy-6-nitrobenzonitrile (46.0 g,    162 mmol), sodium bicarbonate (95.0 g, 1.13 mol), water (750 ml),    dichloromethane (550 ml) and tetrabutylammonium chloride (30.0 g,    108 mmol) was rapidly stirred at 20° C. and treated with sodium    dithionite (66.0 g, 379 mmol) portionwise over 2 hours. The mixture    was stirred for a further 1 hour then the phases separated. The    aqueous phase was extracted with dichloromethane (2×200 ml) and then    the combined organic solution was washed with water (300 ml) and    dried over magnesium sulphate. The solution was concentrated to 250    ml and 4.0N hydrochloric acid in 1,4-dioxane (150 ml, 0.6 mol) was    added. Diethyl ether (1000 ml) was added and the reaction cooled    with ice. The resulting solid was collected by suction filtration    and washed with diethyl ether. The resultant solid was stirred in    methanol (1000 ml), sodium bicarbonate solution (800 ml) was added    (until pH >8) and the reaction was stirred for 1 hour. The solid was    collected by suction filtration, washed with water and methanol and    dried in vacuo to yield 2-cyano-5-benzyloxy-4-methoxyaniline (34 g,    82% yield) as light brown solid:

¹H-NMR (DMSO d₆): 7.40 (m, 5H), 6.90 (s, 1H), 6.50 (s, 1H), 5.60 (br s,2H), 5.02 (s, 2H), 3.65 (s, 3H):

MS (+ve ESI): 254 (M+H)⁺.

-   d) 2-cyano-5-benzyloxy-4-methoxyaniline (100 g, 394 mmol) in toluene    (1400 ml) was heated with dimethylformamide dimethylacetal (100 ml,    940 mmol) at reflux with slow distillation of solvent to maintain    the internal temperature at 105° C. After 3 hours the solution was    cooled and filtered to remove a small amount of solid. The filtrate    was evaporated in vacuo, the residue was triturated with diethyl    ether and the solid collected by suction filtration. Prolonged    drying in vacuo yielded    N′-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (110 g, 90% yield) as a brown solid:

¹H-NMR (DMSO d₆): 7.90 (s, 1H), 7.40 (m, 5H), 7.10 (s, 1H), 6.88 (s,1H), 5.15 (s, 2H), 3.70 (s, 3H), 3.02 (s, 3H), 2.95 (s, 3H):

MS (+ve ESI): 310 (M+H)⁺

MS (−ve ESI): 308 (M−H)⁻.

-   e)    N′-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (110 g, 356 mmol) and trifluoroacetic acid (600 ml) were heated at    reflux for 15 minutes. Evaporation and co-evaporation with toluene,    trituration with diethyl ether and collection of the solid by    suction filtration, followed by prolonged drying in vacuo, yielded    N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide    (112 g, 95% yield) as a light brown trifluoroacetate salt:

¹H-NMR (DMSO d₆): 8.39 (s, 1H), 7.38 (s, 1H), 6.90 (s, 1H), 3.80 (s,3H), 3.25 (s, 3H), 3.17 (s, 3H):

MS (+ve ESI): 220 (M+H)⁺

MS (−ve ESI): 218 (M−H)⁻.

-   f) A mixture of    N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide    (21.9 g, 66 mmol), caesium carbonate (998 g, 300 mmol) and    1-bromo-3-chloropropane (11 ml, 110 mmol) in acetonitrile (300 ml)    was heated at reflux for 1 hour. The reaction mixture was cooled and    the solvent evaporated in vacuo. The residue was dissolved in water    (200 ml) and extracted with dichloromethane (2×150 ml). The organic    solution was washed with brine (50 ml) and dried over magnesium    sulphate. The solvent was evaporated in vacuo and the resultant    solid was triturated (with diethyl ether) and collected by suction    filtration. Drying in vacuo yielded    N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (17.7 g, 91% yield) as a white solid:

¹H-NMR (DMSO d₆): 8.89 (s, 1H), 7.07 (s, 1H), 6.75 (s, 1H), 4.15 (t,2H), 3.77 (t, 2H), 3.70 (s, 3H), 3.05 (s, 3H), 2.95 (s, 3H), 2.18 (m,2H):

MS (+ve ESI): 296.4 (M+H)⁺.

-   g) A mixture of tert-butyl    5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-ylcarbamate    (3.82 g, 10 mmol) and    N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (2.95 g, 10 mmol) in acetic acid (10 ml) was heated at reflux for 2    hours. The mixture was cooled and the solid product collected by    suction filtration, washed with acetic acid then diethyl ether. The    solid was dissolved in dimethyl acetamide (20 ml) and filtered.    Aqueous sodium bicarbonate solution (50 ml) was added slowly to the    filtrate and the solid product was collected by suction filtration,    washed with water and dried to yield    N-(3-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (3.63 g, 73% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.00 (br s, 1H), 10.42 (br s, 1H), 8.63 (s, 1H), 8.10(s, 1H), 7.60 (m, 1H), 7.30 (m, 4H), 6.85 (m, 1H), 4.25 (t, 2H), 3.95(s, 3H), 3.85 (s, 2H), 3.80 (t, 2H), 2.25 (m, 2H):

MS (+ve ESI): 502 (M+H)⁺

MS (−ve ESI): 500 (M−H)⁻.

-   h)    N-(3-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (13.1 g, 26.1 mmol) in dimethyl acetamide (180 ml) was reacted with    piperidin-4-ylmethanol (6.01 g, 52.3 mmol) in the presence of    tetrabutylammonium iodide (1.3 g, 10 mol %) at 60° C., under an    inert atmosphere, for 20 hours. The cooled reaction solution was    diluted with aqueous sodium bicarbonate solution and the resulting    solid was collected by suction filtration. Purification by    chromatography on silica gel, eluting with    methanol:ammonia:dichloromethane (7:1:92), evaporation of solvents    and drying in vacuo yielded    N-(3-fluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (6.01 g, 40% yield) as an orange solid:

¹H-NMR (DMSO d₆): 10.42 (br s, 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.60 (m,1H), 7.35 (m, 3H), 7.20 (s, 1H), 6.85 (m, 1H), 4.35 (t, 1H), 4.17 (t,2H), 3.95 (s, 3H), 3.85 (s, 2H), 3.20 (t, 2H), 2.85 (m, 2H), 2.43 (m,2H), 1.90 (m, 4H), 1.60 (m, 2H), 1.30 (m, 1H), 1.10 (m, 2H):

MS (+ve ESI): 581 (M+H)⁺

MS (−ve ESI): 579 (M−H)⁻.

-   i)    N-(3-fluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (5.41 g, 9.33 mmol) in dimethyl acetamide (50 ml) was treated with    tetrazole (1.33 g, 19.0 mmol) and    di-tert-butyldiethylphosphoramidite (5.8 g, 22 mmol) at 20° C.,    under an inert atmosphere, for 2 hours. The reaction solution was    cooled to −10° C. and 30% hydrogen peroxide solution (2.3 ml, 20    mmol) was added dropwise over 5 minutes. After stirring for 2 hours    at 20° C. the reaction was quenched at −10° C. with 0.5N aqueous    sodium thiosulphate solution. The mixture was extracted twice with    ethyl acetate (300 ml) and the organic solution dried over magnesium    sulphate, evaporated and the resulting oil purified by    chromatography on silica gel, eluting with    methanol:ammonia:dichloromethane (4:1:97). Evaporation of solvent    and drying in vacuo yielded di(tert-butyl)    (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    phosphate (6.66 g, 84% yield) as an orange foam:

¹H-NMR (DMSO d₆): 12.00 (br s, 1H), 10.45 (s, 1H), 8.65 (s, 1H), 8.20(s, 1H), 7.60 (m, 1H), 7.38 (s, 1H), 7.35 (m, 2H), 7.25 (s, 1H), 6.88(m, 1H), 4.18 (m, 2H), 3.95 (s, 3H), 3.89 (s, 2H), 3.70 (m, 2H), 2.90(m, 2H), 2.45 (m, 2H), 1.95 (m, 4H), 1.60 (m, 3H), 1.40 (s, 18H), 1.22(m, 2H):

MS (+ve ESI): 773 (M+H)⁺.

MS (−ve ESI): 771 (M−H)⁻.

tert-butyl5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-ylcarbamate, usedas the starting material (in example 1g) was obtained as follows:

-   j) 2,6-Lutidine (158 g, 1.48 mol) and 10% palladium on carbon (15 g)    were added to a solution of methyl 4-chloro-4-oxobutanoate (220 g,    1.46 mol) in tetrahydrofuran (3600 ml). The mixture was stirred    under a hydrogen atmosphere at 1.6 bar for 7 hours at ambient    temperature. The reaction mixture was filtered through glass fibre    paper washing with diethyl ether. The filtrate was concentrated    under reduced pressure and the residue purified by vacuum    distillation (72° C., 13 mmHg) to yield methyl 4-oxobutanoate (130.8    g, 76% yield) as an oil:

¹H-NMR (DMSO d₆): 9.60 (s, 1H), 3.60 (s, 3H), 2.70 (t, 2H), 2.50 (t,2H).

-   k) Bromine (180 g, 1.12 mol) was added, over 3 hours, to a solution    of methyl 4-oxobutanoate (123.6 g, 1.07 mol) in diethyl ether    (1000 ml) and 1,4-dioxane (9.10 ml) and the reaction mixture stirred    for one hour at ambient temperature. The reaction mixture was poured    into dichloromethane (1000 ml) and calcium carbonate (250 g, 2.50    mol) and sodium hydrogen carbonate (80 g, 0.95 mol) were added    before the mixture was stirred for 21 hours at ambient temperature.    The inorganic solids were removed by suction filtration and the    filtrate was concentrated under reduced pressure to yield methyl    3-bromo-4-oxobutanoate (208 g, quantitative yield) as a brown oil:

¹H-NMR (DMSO d₆): 9.55 (s, 1H), 4.45 (t, 1H), 3.70 (s, 3H), 3.22 (m,1H), 2.95 (m, 1H).

-   l) Methyl 3-bromo-4-oxobutanoate (1.07 mol assumed) was added to a    suspension of thiourea (73 g, 0.96 mol) in methanol, giving an    exotherm. The reaction was heated at 80° C. for 6 hours, cooled and    then allowed to stand at ambient temperature for 4 days. The product    was collected by suction filtration and washed with methanol to give    methyl (2-amino-1,3-thiazol-5-yl)acetate hydrobromide (173 g, 69%    yield) as a yellow crystalline solid:

¹H-NMR (DMSO d₆): 9.25 (bs, 2H), 7.20 (s, 1H), 3.80 (s, 2H), 3.60 (s,3H).

-   m) A solution of di(tert-butyl)dicarbonate (43.9 g, 0.201 mol) in    tetrahydrofuran (200 ml) was added, at 0° C. under a nitrogen    atmosphere, to a solution of methyl    (2-amino-1,3-thiazol-5-yl)acetate hydrobromide (30 g, 0.12 mol) in    tetrahydrofuran (600 ml), water (150 ml) and triethylamine (54 ml,    0.39 mol). Di(tert-butyl)dicarbonate (4.4 g, 20 mmol) and    triethylamine (5.4 ml, 0.039 mol) were added and the reaction    stirred for 20 hours at ambient temperature before the reaction was    concentrated under reduced pressure. The residue was dissolved in    ethyl acetate. The organic phase was washed with brine, dried over    magnesium sulphate, concentrated under reduced pressure and    triturated with diethyl ether and hexane to yield methyl    (2-((tert-butoxycarbonyl)amino)-1,3-thiazol-5-yl)acetate (31.8 g,    98% yield) as a pale orange solid:

¹H-NMR (DMSO d₆): 11.30 (s, 1H), 7.15 (s, 1H), 3.80 (s, 2H), 3.60 (s,3H), 1.40 (s, 9H):

MS (−ve ESI): 271 (M−H)⁻.

-   n) Sodium hydroxide (234 ml of a 1.0 N solution in water) was added    to a solution of methyl    (2-((tert-butoxycarbonyl)amino)-1,3-thiazol-5-yl)acetate (31.8 g,    117 mmol) in tetrahydrofuran (240 ml) and methanol (240 ml). The    solution was stirred overnight at ambient temperature. The organic    solvents were removed under reduced pressure. The residue was    acidified with aqueous citric acid to pH 3.5. The product was    extracted into ethyl acetate, dried over magnesium sulphate,    filtered, concentrated under reduced pressure and triturated with    diethyl ether to give    (2-((tert-butoxycarbonyl)amino)-1,3-thiazol-5-yl)acetic acid (23.1    g, 76% yield) as a pale orange solid:

¹H-NMR (DMSO d₆): 7.10 (s, 1H), 3.70 (s, 2H), 1.40 (s, 9H):

MS (−ve ESI): 257 (M−H)⁻.

-   p) A solution of    (2-((tert-butoxycarbonyl)amino)-1,3-thiazol-5-yl)acetic acid (100 g,    0.388 mol), 3-fluoroaniline (60 g, 0.504 mol) and    diisopropylethylamine (88 ml, 0.504 mol) in dimethylacetamide    (360 ml) under inert and anhydrous conditions, was treated    portionwise with    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluoro-phosphate (191.6 g, 0.504 mol) at 30° C. for 19 hours.    The solvent was removed in vacuo and the residue taken up in ethyl    acetate (1500 ml) and washed with aqueous sodium bicarbonate    solution (500 ml) then water (2×250 ml). The organic solution was    dried over magnesium sulphate, the solvent was removed in vacuo and    the residue was triturated with diethyl ether and dried. The solid    was triturated with dimethyl formamide (500 ml) and a white solid    was collected by filtration, washed with water and dried in vacuo to    yield tert-butyl    5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-ylcarbamate    (78.9 g, 53% yield). The filtrate was diluted with water (1500 ml)    and a light brown solid collected by suction filtration, washed with    water and dried in vacuo to yield a second crop of tert-butyl    5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-ylcarbamate    (51 g, 33% yield):

¹H-NMR (DMSO d₆): 7.58 (m, 1H), 7.30 (m, 2H), 7.15 (s, 1H), 6.85 (m,1H), 3.79 (s, 2H), 1.45 (s, 9H):

MS (+ve ESI): 352 (M+H)⁺

MS (−ve ESI): 350 (M−H)⁻.

EXAMPLE 2 Preparation of Compound 2 in Table1—((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (400 mg, 0.528 mmol) yielded the title compound (313 mg, 81%yield):

¹H-NMR (DMSO d₆): 9.03 (s, 1H), 7.89 (s, 1H), 7.65 (d, 1H), 7.62 (s,1H), 7.44 (s, 1H), 7.44 (s, 1H), 7.36 (m, 2H), 6.90 (m, 1H), 4.32 (m,2H), 4.25 (m, 2H), 4.02 (s, 2H), 3.99 (s, 3H), 3.80 (m, 1H), 3.70 (m,1H), 3.60 (m, 1H), 3.30 (m, 1H), 3.23 (q, 1H), 2.35 (m, 2H), 2.20 (m,1H), 2.04 (m, 1H), 1.96 (m, 1H), 1.83 (m, 1H):

MS (+ve ESI): 647 (M+H)⁺.

di(tert-butyl)((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with (R)-(−)-2-pyrrolidinylmethanol (334 mg, 3.3 mmol)    yielded    N-(3-fluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (66 mg, 53% yield):

¹H-NMR (DMSO d₆): 12.01 (br s, 1H), 10.48 (s, 1H), 8.68 (s, 1H), 8.13(s, 1H), 7.64 (d, 1H), 7.39 (s, 1H), 7.31-7.42 (m, 2H), 7.26 (s, 1H),6.91 (t, 1H), 4.35 (br s, 1H), 4.22 (t, 2H), 3.98 (s, 3H), 3.91 (s, 2H),3.41 (m, 1H), 3.20 (m, 1H), 3.10 (m, 1H), 2.98 (m, 1H), 2.45 (m, 2H),2.18 (m, 1H), 2.82 (m, 1H), 1.96 (m, 2H), 1.67 (m, 2H), 1.57 (m, 1H):

MS (+ve ESI): 567 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (600 mg, 1.06 mmol) yielded di(tert-butyl)    ((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (400 mg, 50% yield):

¹H-NMR (DMSO d₆): 8.67 (s, 1H), 8.11 (s, 1H), 7.63 (d, 1H), 7.38 (s,1H), 7.35 (m, 2H), 7.25 (s, 1H), 6.90 (m, 1H), 4.21 (m, 2H), 3.97 (s,3H), 3.90 (s, 2H), 3.79 (m, 1H), 3.67 (m, 1H), 3.10 (m, 1H), 2.97 (m,1H), 2.70 (m, 1H), 2.50 (m, 1H), 2.23 (q, 1H), 1.97 (m, 2H), 1.88 (m,1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.38 (s, 18H):

MS (+ve ESI): 759 (M+H)⁺.

EXAMPLE 3 Preparation of Compound 3 in Table1—2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethylphosphate (450 mg, 0.57 mmol) yielded the title compound (430 mg, 96%yield):

¹H-NMR (DMSO d₆, CD₃COOD): 8.89 (s, 1H), 7.81 (s, 1H), 7.56 (d, 1H),7.48 (s, 1H), 7.27 (m, 3H), 6.80 (m, 1H), 4.27 (m, 4H), 3.95 (s, 5H),3.67 (m, 8H), 3.47 (m, 2H), 3.39 (t, 2H), 2.34 (m, 2H):

MS (+ve ESI): 676.5 (M+H)⁺.

Di(tert-butyl)2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with 1-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol)    yielded    N-(3-fluorophenyl)-2-(2-((7-3(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (91 mg, 69% yield):

¹H-NMR (DMSO d₆): 12.04 (br s, 1H), 10.48 (s, 1H), 8.68 (s, 1H), 8.12(s, 1H), 7.65 (d, 1H), 7.39 (s, 1H), 7.32-7.42 (m, 2H), 7.25 (s, 1H),6.91 (t, 1H), 4.37 (t, 1H), 4.20 (t, 2H), 3.97 (s, 3H), 3.91 (s, 2H),3.50 (q, 2H), 2.41 (m, 12H), 1.96 (m, 2H):

MS (+ve ESI): 596 (M+H)⁺.

-   b)    N-(3-fluorophenyl)-2-(2-((7-3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (595 mg, 1 mmol) was dissolved in dimethylformamide (3 ml).    Tetrazole (280 mg, 4 mmol) and di-tert-butyl-diethylphosphoramidite    (598 μl, 2 mmol) were added to the mixture at ambient temperature,    and stirring was continued for 2 hours under argon. The mixture was    cooled to −60° C. and a solution of monoperoxyphtalic acid magnesium    salt (371 mg, 0.6 mmol) in dimethylformamide (2 ml) was slowly    added. This mixture was stirred for 1.5 hours at −60° C., sodium    metabisulfite (1.9 g, 10 mmol) in water (2 ml) was added, and the    mixture was slowly allowed to warm to ambient temperature,    evaporated, and purified by chromatography on silica gel, eluting    with dichloromethane: 3.0 N methanolic ammonia (0-10%), to give    di(tert-butyl)    2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    phosphate (600 mg, 76% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.11 (s, 1H), 7.63 (d, 1H), 7.39 (s,1H), 7.34 (t, 2H), 7.25 (s, 1H), 6.91 (t, 1H), 4.19 (t, 2H), 3.97 (s,3H), 3.92 (m, 2H), 3.90 (s, 2H), 2.52 (m, 4H), 2.42 (m, 8H), 1.95 (m,2H), 1.42 (s, 18H):

MS (+ve ESI): 788.6 (M+H)⁺.

EXAMPLE 4 Preparation of Compound 4 in Table1—1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-yldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-ylphosphate (435 mg, 0.58 mmol) yielded the title compound (325 mg, 78%yield):

¹H-NMR (DMSO d₆, CD₃COOD): 9.02 (s, 1H), 7.87 (s, 1H), 7.66 (m, 1H),7.61 (s, 1H), 7.36 (m, 3H), 6.90 (m, 1H), 4.97 (m, 1H), 4.30 (m, 2H),3.97 (s, 2H), 3.90 (s, 3H), 3.75 (m, 1H), 3.40 (m, 3H), 3.26 (m, 1H),2.45 (m, 1H), 2.31 (m, 3H), 2.18 (m, 1H):

MS(+ve ESI): 633.5 (M+H)⁺.

Di(tert-butyl)1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-ylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with 3-pyrrolidinol (288 mg, 3.3 mmol) yielded    N-(3-fluorophenyl)-2-(2-((7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (18 mg, 15% yield):

¹H-NMR (DMSO d₆, TFA): 9.09 (s, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 7.63(d, 1H), 7.31-7.41 (m, 2H), 7.28 (d, 1H), 6.91 (m, 1H), 4.41-4.51 (m,1H), 4.29 (m, 2H), 4.00 (s, 2H), 3.99 (s, 3H), 3.02-3.79 (m, 6H), 2.27(m, 2H), 1.84-2.03 (m, 2H):

MS (+ve ESI): 553 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (552 mg, 1 mmol) yielded di(tert-butyl)    1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-yl    phosphate (440 mg, 59% yield).

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.13 (s, 1H), 7.63 (d, 1H), 7.39 (s,1H), 7.35 (m, 2H), 7.25 (s, 1H), 6.91 (m, 1H), 4.76 (m, 1H), 4.22 (t,2H), 3.98 (s, 3H), 3.90 (s, 2H), 2.75 (m, 3H), 2.63 (m, 2H), 2.45 (m,1H), 2.16 (m, 1H), 1.98 (m, 2H), 1.85 (m, 1H), 1.40 (s, 18H):

MS (+ve ESI): 745.6 (M+H)⁺.

EXAMPLE 5 Preparation of Compound 5 in Table1—1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-3-yldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-3-ylphosphate (470 mg, 0.62 mmol) yielded the title compound (340 mg, 75%yield):

¹H-NMR (DMSO d₆, CD₃COOD): 9.05 (s, 1H), 7.86 (s, 1H), 7.64 (m, 1H),7.63 (s, 1H), 7.37 (m, 3H), 6.90 (m, 1H), 4.55-4.67 (m, 1H), 4.30 (m,2H), 4.02 (s, 2H), 3.90 (s, 3H), 3.60 (m, 1H), 3.47 (m, 1H), 3.30 (m,2H), 3.00 (m, 2H), 1.50-2.40 (m, 6H):

MS (+ve ESI): 647.6 (M+H)⁺.

Di(tert-butyl)1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-ylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with 3-hydroxypiperidine (334 mg, 3.3 mmol) yielded    N-(3-fluorophenyl)-2-(2-((7-(3-(3-hydroxypiperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (72 mg, 58% yield):

¹H-NMR (DMSO d₆): 12.02 (br s, 1H), 10.48 (s, 1H), 8.68 (s, 1H), 8.13(br s, 1H), 7.64 (s, 1H), 7.40 (s, 1H), 7.31-7.42 (m, 2H), 7.26 (s, 1H),6.91 (t, 1H), 4.60 (d, 1H), 4.20 (t, 2H), 3.98 (s, 3H), 3.91 (s, 2H),3.49 (m, 1H), 2.85 (m, 1H), 2.69 (m, 1H), 2.47 (m, 2H), 1.96 (t, 2H),1.87 (m, 1H), 1.78 (m, 2H), 1.63 (m, 1H), 1.43 (m, 1H), 1.09 (m, 1H):

MS (+ve ESI): 567 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-(3-hydroxypiperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (680 mg, 1.2 mmol) yielded di(tert-butyl)    1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-3-yl    phosphate (500 mg, 55% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.12 (s, 1H), 7.63 (d, 1H), 7.35 (m,3H), 7.25 (s, 1H), 6.90 (m, 1H), 3.97 (s, 3H), 3.90 (s, 2H), 3.40 (m,1H), 2.90 (m, 1H), 2.60 (m, 1H), 2.50 (m, 1H), 2.20 (m, 2H), 1.95 (m,3H), 1.70 (m, 1H), 1.45 (m, 2H), 1.39 (s, 18H):

MS (+ve ESI): 759.6 (M+H)⁺.

EXAMPLE 6 Preparation of Compound 6 in Table1—2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethylphosphate (284 mg, 0.38 mmol) yielded the title compound (270 mg, 38%yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.90 (s, 1H), 7.64 (s, 1H), 7.62(m, 1H), 7.36 (m, 3H), 6.90 (m, 1H), 4.30 (m, 2H), 4.22 (m, 2H), 3.99(s, 2H), 3.98 (s, 3H), 3.48 (m, 2H), 3.35 (m, 4H), 2.28 (m, 2H), 1.27(t, 3H):

MS (+ve ESI): 635 (M+H)⁺.

Di(tert-butyl)2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with    2-(2-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (2 g, 4 mmol) and 2-(ethylamino)ethanol (2 ml, 20 mmol) yielded    N-(3-fluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)(ethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (1.49 g, 67% yield):

¹H-NMR (DMSO d₆, TFA): 9.09 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.61(d, 1H), 7.35 (m, 2H), 7.3 (s, 1H), 6.91 (m, 1H), 4.3 (t, 2H), 4.00 (s,2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.3 (m, 6H), 2.28 (m, 2H), 1.26 (t,3H):

MS (+ve ESI): 555.6 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)(ethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (560 mg, 1 mmol) yielded di(tert-butyl)    2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    phosphate (255 mg, 34% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.12 (s, 1H), 7.63 (m, 1H), 7.37 (m,3H), 7.24 (s, 1H), 6.90 (m, 1H), 4.21 (t, 2H), 3.97 (s, 3H), 3.90 (s,2H), 3.87 (m, 2H), 2.64 (m, 6H), 1.92 (m, 2H), 1.39 (s, 18H), 0.98 (t,3H):

MS (+ve ESI): 747.6 (M+H)⁺.

EXAMPLE 7 Preparation of Compound 7 in Table1—((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

Hydrochloric acid (10.4 ml of a 4.0 N solution in 1,4-dioxane, 41.5mmol) was added, dropwise to a solution of di(tert-butyl)((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (4.49 g, 5.92 mmol) in 1,4-dioxane (180 ml) upon which a lightyellow solid precipitated from the reaction mixture. The resultingheterogeneous reaction mixture was stirred for a further 20 hours beforethe precipitate was collected, washed with 1,4-dioxane (80 ml) andacetonitrile (2×100 ml) and dried in vacuo to yield((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate bis-hydrochloride as a light yellow solid (4.40 g,97% yield):

¹H-NMR (DMSO d₆): 10.96 (s, 1H), 9.05 (s, 1H), 7.82 (s, 1H), 7.62 (m,2H), 7.38 (m, 3H), 6.90 (t, 1H), 4.25 (m, 4H), 4.05 (s, 2H), 3.96 (s,3H), 3.80 (m, 1H), 3.69 (m, 1H), 3.60 (m, 1H), 3.28 (m, 1H), 3.19 (q,1H), 2.35 (m, 2H), 2.20 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.81 (m,1H):

³¹P-NMR (DMSO d₆): −0.04 (s, 1P):

MS (+ve ESI): 647 (M+H)⁺.

Di(tert-butyl)((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with (S)-(+)-2-pyrrolidinylmethanol (334 mg, 3.3 mmol)    yielded    N-(3-fluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (59 mg, 48% yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 7.63(d, 1H), 7.30-7.40 (m, 2H), 7.29 (s, 1H), 6.89 (t, 1H), 4.29 (t, 2H),3.99 (s, 2H), 3.98 (s, 3H), 3.77 (q, 1H), 3.61 (m, 4H), 3.23 (m, 2H),2.31 (m, 2H), 2.13 (m, 1H), 2.03 (m, 1H), 1.90 (m, 1H), 1.78 (m, 1H):

MS (+ve ESI): 567 (M+H)⁺.

-   b) 1H-tetrazole (897 mg, 12.8 mmol) and di-tert-butyl    diethylphosphoramidite (4.37 ml, 15.7 mmol) were added, directly to    a stirred mixture of    N-(3-fluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (3.63 g, 6.41 mmol) in dry dimethylacetamide (35 ml) maintained    under a nitrogen atmosphere. After stirring for 2 hours, further    equivalents of 1H-tetrazole (897 mg, 12.8 mmol) and di-tert-butyl    diethylphosphoramidite (4.37 ml, 15.7 mmol) were added. Stirring was    continued for a further 2 hours upon which time the reaction mixture    was cooled (−10° C.) and hydrogen peroxide (4.16 ml of a 30% w/w    aqueous solution, 36.6 mmol) was introduced dropwise then the    reaction mixture warmed to ambient temperature over 10 minutes and    stirred for a further 18 hours. The reaction was then cooled (0° C.)    and quenched with sodium thiosulphite (0.53 N aqueous solution)    until the reaction mixture tested negative for peroxide. The    reaction mixture was then diluted with ethyl acetate (200 ml) and    sodium hydrogen carbonate (100 ml of a saturated aqueous solution)    was added, the phases separated and the aqueous layer further    extracted with ethyl acetate (3×100 ml). The combined organic layers    were dried over sodium sulphate, filtered and concentrated under    reduced pressure to afford a yellow oil. This material was subjected    to chromatography on silica gel, eluting with    methanol:dichloromethane (0-10%) and concentration of the    appropriate fractions yielded di(tert-butyl)    ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (as a yellow foam) which was used in the next step of the    reaction sequence:

MS (+ve ESI): 759 (M+H)⁺.

EXAMPLE 8 Preparation of Compound 8 in Table1—2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethylphosphate (230 mg, 0.277 mmol) yielded the title compound (199 mg, 100%yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.63(m, 1H), 7.41 (s, 1H), 7.35 (m, 2H), 6.90 (m, 1H), 4.32 (m, 2H), 4.28(m, 2H), 3.88 (d, 1H), 3.72 (m, 2H), 3.6 (m, 2H), 3.52 (m, 2H), 3.37 (q,2H), 3.27 (m, 2H), 2.38 (m, 3H), 2.07 (m, 2H), 1.98 (m, 1H), 1.29 (t,3H):

MS (+ve ESI): 718.4 (M+H)⁺.

Di(tert-butyl)2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethylphosphate used as the starting material was obtained as follows:

-   a) tert-butyl    (2S)-2-(((methylsulfonyl)oxy)methyl)pyrrolidin-1-ylcarboxylate (4.75    g, 17 mmol) was condensed with 2-(ethylamino)ethanol (8.3 ml, 85.1    mmol) at 65° C. for 4 hours and over night at ambient temperature.    The crude reaction mixture was purified by chromatography on silica    gel, eluting with dichloromethane:7.0N methanolic ammonia (0-7%), to    give tert-butyl    (2S)-2-((ethyl(2-hydroxyethyl)amino)methyl)pyrrolidin-1-ylcarboxylate    (1.54 g, 33% yield):

¹H-NMR (DMSO d₆): 4.30 (t, 1H), 3.68 (m, 1H), 3.42 (m, 2H), 3.20 (m,2H), 2.51 (m, 4H), 2.21 (t, 1H), 1.80 (m, 4H), 1.42 (s, 9H), 0.96 (t,3H).

-   b) tert-butyl    (2S)-2-((ethyl(2-hydroxyethyl)amino)methyl)pyrrolidin-1-ylcarboxylate    (1.52 g, 5.58 mmol) in solution in dioxane (20 ml) was treated with    a solution of hydrochloric acid (4.0 N) in dioxane (6 ml, 24 mmol)    at ambient temperature for 18 hours. The solvent was evaporated, and    the residue was taken up in a mixture of dichloromethane:methanol    (9:1) and was treated with 7.0N methanolic ammonia (10 ml, 70 mmol).    The solid was removed by filtration, and the residue was purified by    chromatography on silica gel, eluting with dichloromethane:7.0N    methanolic ammonia (0-12%), to give    2-(ethyl((2S)-pyrrolidin-2-ylmethyl)amino)ethanol (950 mg, 99%    yield):

¹H-NMR (DMSO d₆, TFA): 3.97 (m, 1H), 3.78 (m, 2H), 3.55 (m, 2H), 3.27(m, 6H), 2.22 (m, 1H), 1.98 (m, 1H), 1.90 (m, 1H), 1.70 (m, 1H), 1.26(t, 3H):

MS (+ve ESI): 173.4 (M+H)⁺.

-   c)    2-(2-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (1.4 g, 2.79 mmol) in N-methyl pyrrolidine (2 ml) was condensed with    2-(ethyl((2S)-pyrrolidin-2-ylmethyl)amino)ethanol (1.45 g, 8.42    mmol) at 85° C. for 10 hours. The solvent was evaporated, and the    crude was purified by chromatography on silica gel, eluting with    dichloromethane:7.0N methanolic ammonia (0-8%), to give    2-(2-((7-(3-((2S)-2-((ethyl(2-hydroxyethyl)amino)methyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (670 mg, 37% yield):

¹H-NMR (DMSO d₆): 4.21 (m, 2H), 3.97 (s, 3H), 3.90 (s, 2H), 3.41 (m,2H), 3.10 (m, 2H), 2.46 (m, 6H), 2.32 (m, 1H), 2.20 (m, 1H), 2.12 (q,1H), 1.95 (m, 2H), 1.83 (m, 1H), 1.67 (m, 2H), 1.50 (m, 1H), 0.90 (t,3H):

MS (+ve ESI): 638.6 (M+H)⁺.

-   d) An analogous reaction to that described in example 1i, but    starting with    2-(2-((7-(3-((2S)-2-((ethyl(2-hydroxyethyl)amino)methyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (650 mg, 1.02 mmol) yielded di(tert-butyl)    2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyl    phosphate (235 mg, 28% yield):

¹H-NMR (DMSO d₆): 8.67 (s, 1H), 8.11 (s, 1H), 7.63 (m, 1H), 7.38 (m,3H), 7.24 (s, 1H), 6.90 (m, 1H), 4.20 (m, 2H), 3.97 (s, 3H), 3.90 (s,2H), 3.82 (q, 1H), 3.10 (m, 2H), 2.55 (m, 7H), 2.32 (m, 1H), 2.22 (m,1H), 2.10 (q, 1H), 1.95 (m, 2H), 1.83 (m, 1H), 1.65 (m, 2H), 1.52 (m,1H), 1.40 (s, 18H), 0.91 (t, 3H):

MS (+ve ESI): 830 (M+H)⁺.

EXAMPLE 9 Preparation of Compound 9 in Table1—1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylphosphate (650 mg, 0.85 mmol) yielded the title compound (553 mg, 100%yield):

¹H-NMR (DMSO d₆): 9.06 (s, 1H), 7.90 (s, 1H), 7.65 (m, 1H), 7.64 (s,1H), 7.40 (s, 1H), 7.32 (m, 2H), 6.91 (m, 1H), 4.55 (m, 1H), 4.32 (m,2H), 3.99 (s, 3H), 3.58 (s, 3H), 3.48 (m, 2H), 3.28 (m, 2H), 3.10 (m,2H), 2.35 (m, 2H), 2.15 (m, 2H), 2.05 (m, 2H):

MS (+ve ESI): 647.5 (M+H)⁺.

di(tert-butyl)1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with 4-hydroxypiperidine (334 mg, 3.3 mmol) yielded    N-(3-fluorophenyl)-2-(2-((7-(3-(4-hydroxypiperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (21 mg, 17% yield):

¹H-NMR (DMSO d₆, TFA): 9.09 (s, 1H), 7.91 (s, 1H), 7.64 (s,1H), 7.63 (d,1H), 7.30-7.40 (m, 2H), 7.29 (s, 1H), 6.90 (t, 1H), 4.28 (t, 2H), 3.99(s, 2H), 3.98 (s, 3H), 3.68 (m, 1H), 3.57 (d, 1H), 3.40 (m, 1H), 3.28(m, 2H), 3.21 (m, 1H), 3.03 (t, 1H), 2.28 (m, 2H), 2.01 (d, 1H), 1.85(m, 2H), 1.59 (m, 1H):

MS (+ve ESI): 567 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-(4-hydroxypiperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (900 mg, 1.59 mmol) yielded di(tert-butyl)    1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4yl    phosphate (700 mg, 58% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.12 (s, 1H), 7.62 (m, 1H), 7.39 (s,1H), 7.35 (m, 2H), 7.26 (s, 1H), 6.92 (m, 1H), 4.21 (m, 2H), 3.97 (s,3H), 3.90 (s, 2H), 3.38 (m, 1H), 2.56 (m, 2H), 2.46 (t, 2H), 2.25 (m,2H), 1.96 (m, 2H), 1.87 (m, 2H), 1.67 (m, 2H), 1.42 (s, 18 H):

MS (+ve ESI): 759.7 (M+H)⁺.

EXAMPLE 10 Preparation of Compound 10 in Table1—2-((((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withtert-butyl2-((di(tert-butoxy)phosphoryl)oxy)ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)carbamate(535 mg, 0.67 mmol) yielded the title compound (416 mg, 68% yield):

¹H-NMR (DMSO d₆, TFA): 9.07 (s, 1H), 7.90 (s, 1H), 7.64 (s, 1H), 7.62(m, 1H), 7.40 (s, 1H), 7.38 (m, 2H), 6.90 (m, 1H), 4.32 (m, 2H), 4.16(m, 2H), 4.00 (s, 2H), 3.99 (s, 3H), 3.82 (m, 1H), 3.68 (m, 3H), 3.43(m, 1H), 3.32 (m, 4H), 2.35 (m, 3H), 2.20 (m, 3H):

MS (+ve ESI): 690.5 (M+H)⁺.

tert-butyl2-((di(tert-butoxy)phosphoryl)oxy)ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)carbamateused as the starting material was obtained as follows:

-   a) tert-butyl    (2S)-2-(((methylsulfonyl)oxy)methyl)pyrrolidin-1-ylcarboxylate (7 g,    25 mmol) was reacted with ethanolamine (7.5 ml, 124 mmol) at 85° C.    for 2 hours. The crude reaction mixture was purified by    chromatography on silica gel, eluting with dichloromethane:7.0N    methanolic ammonia (0-6%), to give tert-butyl    (2S)-2-(((2-hydroxyethyl)amino)methyl)pyrrolidin-1-ylcarboxylate    (3.56 g, 58% yield):

¹H-NMR (DMSO d₆, TFA): 4.03 (m, 1H), 3.66 (m, 2H), 3.28 (m, 2H), 3.03(m, 4H), 1.82 (m, 4H), 1.44 (s, 9H):

MS (+ve ESI): 245.6 (M+H)⁺.

-   b) tert-butyl    (2S)-2-(((2-hydroxyethyl)amino)methyl)pyrrolidin-1-ylcarboxylate    (3.55 g, 14.5 mmol) in dioxane (10 ml) was treated with a solution    of hydrochloric acid (4.0 N) in dioxane (20 ml, 5.5 eq) for 20 hours    at ambient temperature. The dioxane was evaporated, the residue was    dissolved in methanol and treated with 7.0 N methanolic ammonia (10    ml, 70 mmol). The solid was collected by suction filtration and,    after evaporation of the solvent, the residual oil was purified by    chromatography on HP20SS support, eluting with water:aqueous    potassium carbonate solution (6.0 N). The fractions containing    compound were collected, evaporated and the residue extracted with    dichloromethane:methanol before the organic phase was dried and    concentrated in vacuo to yield    2-(((2S)-pyrrolidin-2-ylmethyl)amino)ethanol (1.99 g, 95% yield):

¹H-NMR (DMSO d₆, TFA): 3.84 (m, 1H), 3.69 (t, 2H), 3.30 (m, 4H), 3.10(m, 2H), 2.15 (m, 1H), 1.92 (m, 2H), 1.72 (m, 1H):

MS (+ve ESI): 145.3 (M+H)⁺.

-   c)    2-(2-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (1 g, 2 mmol) in solution in N-methyl pyrrolidine (4 ml) was reacted    with 2-(((2S)-pyrrolidin-2-ylmethyl)amino)ethanol (1.15 g, 8 mmol)    at 85° C. for 2.5 hours. The crude mixture was purified by    chromatography on silica gel, eluting with dichloromethane:7.0N    methanolic ammonia (0-10%), to yield    N-(3-fluorophenyl)-2-(2-((7-(3-((2S)-2-(((2-hydroxyethyl)amino)methyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (0.77 g, 64% yield):

¹H-NMR (DMSO d₆, TFA): 9.09 (s, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.62(m, 1H), 7.36 (m, 3H), 6.90 (m, 1H), 4.31 (m, 2H), 4.00 (s, 2H), 3.99(s, 3H), 3.77 (m, 3H), 3.70 (t, 2H), 3.60 (m, 2H), 3.30 (m, 3H), 3.13(m, 2H), 2.33 (m, 2H), 2.00 (m, 3H):

MS (+ve ESI): 610.6 (M+H)⁺.

-   d)    N-(3-fluorophenyl)-2-(2-((7-(3-((2S)-2-(((2-hydroxyethyl)amino)methyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (760 mg, 1.25 mmol) in dimethylformamide (5 ml) and dichloromethane    (10 ml) was reacted with di-tert-butyl dicarbonate (300 mg, 1.37    mmol). The mixture was stirred at ambient temperature for 18 hours,    the solvent was evaporated and the residue purified by    chromatography on silica gel, eluting with dichloromethane:7.0N    methanolic ammonia (0-6%), to give tert-butyl    ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl(2-hydroxyethyl)carbamate    (517 mg, 58% yield):

¹H-NMR (DMSO d₆): 8.65 (s, 1H), 8.10 (s, 1H), 7.61 (d, 1H), 7.37 (s,1H), 7.32 (m, 2H), 7.23 (s, 1H), 6.90 (m, 1H), 4.19 (m, 2H), 3.95 (s,3H), 3.89 (s, 2H), 3.42 (m, 4H), 3.25 (m, 1H), 3.17 (m, 1H), 3.09 (m,1H), 2.95 (m, 1H), 2.60 (m, 1H), 2.37 (m, 1H), 2.18 (q, 1H), 1.97 (m,2H), 1.80 (m, 1H), 1.68 (m, 2H), 1.50 (m, 1H):

MS (+ve ESI): 710.5 (M+H)⁺.

-   e) An analogous reaction to that described in example 1i, but    starting with tert-butyl    ((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl(2-hydroxyethyl)carbamate    (510 mg, 0.72 mmol) yielded tert-butyl    2-((di(tert-butoxy)phosphoryl)oxy)ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)carbamate    (535 mg, 93% yield):

¹H-NMR (DMSO d₆): 8.66 (s, 1H), 8.10 (s, 1H), 7.61 (d, 1H), 7.37 (s,1H), 7.33 (m, 2H), 7.20 (s, 1H), 6.90 (m, 1H), 4.18 (m, 2H), 3.95 (s,3H), 3.88 (m, 4H), 3.40 (m, 2H), 3.09 (m, 2H), 2.95 (m, 2H), 2.60 (m,1H), 2.37 (m, 1H), 2.18 (m, 1H), 1.98 (m, 2H), 1.78 (m, 1H), 1.70 (m,2H), 1.52 (m, 1H), 1.38 (s, 18H), 1.34 (s, 9H).

EXAMPLE 11 Preparation of Compound 11 in Table1—2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 1 but starting withtert-butyl2-((di(tert-butoxy)phosphoryl)oxy)ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)carbamate(350 mg, 0.428 mmol) yielded the title compound (290 mg, 72% yield):

¹H-NMR (DMSO d₆, CD₃COOD): 8.99 (s, 1H), 7.89 (s, 1H), 7.64 (d, 1H),7.60 (s, 1H), 7.37 (m, 3H), 6.89 (m, 1H), 4.31 (m, 2H), 4.16 (m, 2H),4.01 (s, 2H), 3.99 (s, 3H), 3.26 (m, 2H), 3.20 (m, 2H), 2.27 (m, 2H):

MS (+ve ESI): 607.4 (M+H)⁺.

tert-butyl2-((di(tert-butoxy)phosphoryl)oxy)ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)carbamateused as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with    2-(2-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (249 mg, 0.4 mmol) and ethanolamine (122 mg, 2 mmol) yielded    N-((3-fluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide,    (90 mg, 43% yield):

¹H-NMR (DMSO d₆): 8.67 (s, 1H), 8.11 (s, 1H), 7.63 (d, 1H), 7.38 (s,1H),7.35 (m, 2H), 7.26 (s, 1H), 6.91 (t,1H), 4.23 (t, 2H), 3.97 (s, 3H),3.90 (s, 2H), 3.47 (t, 2H), 2.72 (t, 2H), 2.62 (t, 2H), 1.95 (m, 2H):

MS (+ve ESI): 527.59 (M+H)⁺.

-   b) A solution of    N-((3-fluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (650 mg, 1.23 mmol) in dimethylformamide (5 ml) was reacted with    di-tert-butyl dicarbonate (590 mg, 2.7 mmol) at 50° C. for 48 hours.    The solvent was evaporated and the residue purified by    chromatography on silica gel, eluting with dichloromethane:3.0 N    methanolic ammonia (0-5%), to yield tert-butyl    3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl(2-hydroxyethyl)carbamate    (330 mg, 43% yield):

¹H-NMR (DMSO d₆, TFA): 8.68 (s, 1H), 8.12 (s, 1H), 7.62 (d, 1H), 7.36(m, 3H), 7.24 (s, 1H), 6.90 (m, 1H), 4.68 (m, 2H), 4.14 (m, 2H), 3.96(s, 3H), 3.89 (s, 2H), 3.47 (m, 2H), 3.24 (m, 2H), 2.02 (m, 2H), 1.35(m, 9H):

MS (+ve ESI): 627.5 (M+H)⁺.

-   c) An analogous reaction to that described in example 1i, but    starting with tert-butyl    3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl(2-hydroxyethyl)carbamate    (330 mg, 0.53 mmol) yielded tert-butyl    2-((di(tert-butoxy)phosphoryl)oxy)ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)carbamate    (350 mg, 81% yield):

¹H-NMR (DMSO d₆, TFA): 9.40 (s, 1H), 9.07 (s, 1H), 7.61 (m, 2H), 7.35(m, 2H), 7.24 (s, 1H), 6.89 (t, 1H), 4.19 (t, 2H), 3.96 (m, 7H), 3.41(m, 4H), 2.05 (m, 2H), 1.40 (m, 27H).

EXAMPLE 12 Preparation of Compound 12 in Table1—3-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)propyldihydrogen phosphate

An analogous reaction to that described in example 1 but starting withdi(tert-butyl)3-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)propylphosphate (430 mg, 0.56 mmol) yielded the title compound (415 mg, 99%yield):

¹H-NMR (DMSO d₆, CD₃COOD): 9.04 (s, 1H), 7.88 (s, 1H), 7.63 (m, 2H),7.36 (m, 3H), 6.90 (m, 1H), 4.31 (m, 2H), 4.00 (m, 7H), 3.25 (m, 6H),2.32 (m, 2H), 2.07 (m, 2H), 1.30 (t, 3H).

di(tert-butyl)3-(ethyl(3-((4((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)propylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with    2-(2-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (1 g, 2 mmol) and 3-(ethylamino)propan-1-ol (687 mg, 3 mmol) yielded    2-(2-((7-(3-(ethyl(3-hydroxypropyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide,    (520 mg, 46% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.12 (s, 1H), 7.63 (d, 1H), 7.39 (s,1H), 7.36 (m, 2H), 7.24 (s, 1H), 6.91 (m, 1H), 4.20 (t, 2H), 3.97 (s,3H), 3.90 (s, 2H), 3.42 (t, 2H), 2.56 (m, 2H), 2.47 (m, 4H), 1.92 (m,2H), 1.53 (m, 2H), 0.96 (t, 3H):

MS (+ve ESI): 569.5 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    2-(2-((7-(3-(ethyl(3-hydroxypropyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (470 mg, 0.827 mmol) yielded di(tert-butyl)    3-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)propyl    phosphate (430 mg, 68% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.12 (s, 1H), 7.63 (m, 1H), 7.37 (m,3H), 7.24 (s, 1H), 6.91 (m, 1H), 4.20 (t, 2H), 3.97 (s, 3H), 3.90 (s,2H), 3.85 (q, 2H), 2.50 (m, 6H), 1.91 (m, 2H), 1.70 (m, 2H), 1.37 (s,18H), 0.97 (t, 3H):

EXAMPLE 13 Preparation of Compound 13 in Table1—2-((2-fluoroethyl)(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-((2-fluoroethyl)(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethylphosphate (635 mg, 0.83 mmol) yielded the title compound (550 mg, 80%yield):

¹H-NMR (DMSO d₆, TFA): 9.07 (s, 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.62(m, 1H), 7.34 (m, 3H), 6.90 (m, 1H), 4.98 (m, 1H), 4.87 (m, 1H), 4.30(m, 4H), 3.99 (s, 2H), 3.98 (s, 3H), 3.73 (m, 1H), 3.66 (m, 1H), 3.58(m, 2H), 3.48 (m, 2H), 2.33 (m, 2H):

MS (+ve ESI): 653.5 (M+H)⁺.

Di(tert-butyl)2-((2-fluoroethyl)(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethylphosphate used as the starting material was obtained as follows:

-   a)    2-(2-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (1.26 g, 2.5 mmol) in N-methyl pyrrolidine (5 ml) was reacted with    2-((2-fluoroethyl)amino)ethanol (1.07 g, 10 mmol) at 90° C. for 16    hours. The reaction was purified by chromatography on silica gel,    eluting with dichloromethane:7.0 N methanolic ammonia (3-4%), to    yield    2-(2-((7-(3-((2-fluoroethyl)(2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (0.506 g, 35% yield):

¹H-NMR (DMSO d₆): 8.57 (s, 1H), 8.01 (s, 1H), 7.53 (d, 1H), 7.28 (m,3H), 7.14 (s, 1H), 6.81 (M, 1H), 4.45 (t, 1H), 4.33 (t, 1H), 4.28 (m,1H), 4.11 (t, 2H), 3.87 (s, 3H), 3.80 (s, 2H), 3.36 (m, 2H), 2.74 (t,1H), 2.68 (t, 1H), 2.61 (t, 1H), 2.50 (t, 2H):

MS (+ve ESI): 573.5 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    2-(2-((7-(3-((2-fluoroethyl)(2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (493 mg, 0.86 mmol) yielded di(tert-butyl)    2-((2-fluoroethyl)(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    phosphate (635 mg, 97% yield):

¹H-NMR (DMSO d₆): 8.67 (s, 1H), 8.11 (s, 1H), 7.63 (d, 1H), 7.39 (s,1H), 7.34 (m, 2H), 6.90 (m, 1H), 4.55 (t, 1H), 4.44 (t, 1H), 4.21 (t,2H), 3.97 (2, 3H), 2.87 (t, 1H), 2.78 (m, 3), 2.74 (t, 2H), 1.94 (m,2H), 1.39 (s, 18H):

MS (+ve ESI): 765.5 (M+H)⁺.

EXAMPLE 14 Preparation of Compound 14 in Table1—2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 1 but starting withdi(tert-butyl)-2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethylphosphate (300 mg, 0.42 mmol) yielded the title compound (300 mg, 95%yield):

¹H-NMR (DMSO d₆, CD₃COOD): 9.00 (s, 1H), 7.86 (s, 1H), 7.62 (m, 1H),7.58 (s, 1H), 7.34 (m, 3H), 6.87 (m, 1H), 4.28 (m, 2H), 4.01 (s, 2H),3.96 (s, 3H), 3.92 (m, 2H), 3.55 (d, 2H), 3.23 (t, 2H), 2.93 (t, 2H),2.33 (m, 2H), 1.90 (d, 2H), 1.70 (m, 2H):

MS (+ve ESI): 675.3 (M+H)⁺.

di(tert-butyl)-2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h but    starting with 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol)    yielded    N-(3-fluorophenyl)-2-(2-((7-(3-(4-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (65 mg, 50% yield):

¹H-NMR (DMSO d₆): 12.03 (s, 1H), 10.48 (s, 1H), 8.68 (s, 1H), 8.12 (brs, 1H), 7.63 (d, 1H), 7.40 (s, 1H), 7.32-7.42 (m, 2H), 7.25 (s, 1H),6.91 (t, 1H), 4.33 (t, 1H), 4.20 (t, 2H), 3.97 (s, 3H), 3.91 (s, 2H),3.44 (m, 2H), 2.87 (d, 2H), 1.96 (m, 2H), 1.88 (m, 2H), 1.63 (d, 2H),1.36 (m, 3H), 1.15 (m, 2H):

MS (+ve ESI): 595 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-(4-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (500 mg, 0.84 mmol) yielded    di(tert-butyl)-2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    phosphate (330 mg, 50% yield):

¹H-NMR (DMSO d₆): 8.66 (s, 1H), 8.10 (s, 1H), 7.61 (d, 1H), 7.39 (s,1H), 7.33 (m, 2H), 7.23 (s, 1H), 6.89 (t, 2H), 4.18 (t, 2H), 3.88 (s,3H), 3.86 (m, 4H), 2.86 (d, 2H), 2.42 (t, 2H), 1.88 (m, 2H), 1.85 (t,2H), 1.63 (d, 2H), 1.52 (m, 2H), 1.39 (s, 18H), 1.14 (m, 3H):

MS (+ve ESI): 787.5 (M+H)⁺.

EXAMPLE 15 Preparation of Compound 15 in Table1—2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethylphosphate (360 mg, 0.463 mmol) yielded the title compound (341 mg, 100%yield):

¹H-NMR (DMSO d₆, TFA): 9.06 (s, 1H), 7.92 (s, 1H), 7.62 (d, 1H), 7.60(s, 1H), 6.83 (m, 1H), 6.32 (m, 2H), 6.28 (s, 1H), 4.30 (m, 4H), 3.98(s, 5H), 3.72 (m, 2H), 3.56 (m, 2H), 3.50 (m, 2H), 3.42 (m, 2H), 2.30(m, 2H):

MS (+ve ESI): 665.2 (M+H)⁺.

di(tert-butyl)2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethylphosphate used as the starting material was obtained as follows:

-   a)    2-(2-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (2 g, 4 mmol) in dimethylacetamide (15 ml) was reacted with    2-((2-methoxyethyl)amino)ethanol (1.9 g, 16 mmol) and potassium    iodide (1.32 g, 8 mmol) under argon at 70° C. for 4 hours. The    solvent was evaporated, and the residue was purified by    chromatography on silica gel, eluting with dichloromethane:7.0N    methanolic ammonia (2-5%), to yield    N-(3-fluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)(2-methoxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (1.0 g, 43% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H) 8.12 (s, 1H), 7.63 (d, 1H), 4.21 (t, 2H),3.98 (s, 3H), 3.91 (s, 2H), 3.43 (m, 2H), 3.38 (m, 2H), 2.68 (m, 4H),2.54 (t, 2H), 1.90 (m, 2H):

MS (+ve ESI): 585.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)(2-methoxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (900 mg, 1.54 mmol) yielded di(tert-butyl)    2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethyl    phosphate (360 mg, 30% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.14 (s, 1H), 7.63 (d, 1H), 7.37 (m,3H), 7.25 (s, 1H), 6.90 (m, 1H), 4.21 (m, 2H), 3.97 (s, 3H), 3.91 (s,2H), 3.88 (m, 2H), 3.40 (m, 2H), 3.32 (m, 2H), 3.22 (s, 3H), 2.70 (m,4H), 1.92 (m, 2H), 1.40 (s, 18H):

MS (+ve ESI): 777.4 (M+H)⁺.

EXAMPLE 16 Preparation of Compound 16 in Table1—2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethylphosphate (110 mg, 0.14 mmol) yielded the title compound (85 mg, 82%yield):

¹H-NMR (DMSO-d₆): 10.70 (s, 1H), 9.0 (s, 1H), 7.90 (s, 1H), 7.50-7.60(m, 2H), 7.30-7.40 (m, 3H), 6.90 (m, 1H), 4.40 (t, 2H), 4.00 (s, 3H),3.99 (s, 2H), 3.95 (m, 1H), 3.60-3.70 (m, 1H), 3.40-3.50 (m, 3H),3.10-3.20 (m, 2H), 2.30-2.40 (m, 4H), 1.90-2.10 (m, 3H), 1.70-1.80 (m,1H):

MS (+ve ESI): 661 (M+H)⁺.

di(tert-butyl)2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with (S)-2-(2-hydroxyethyl)pyrrolidine (689 mg, 5.99 mmol)    yielded    N-(3-fluorophenyl)-2-(2-((7-(3-((2S)-2-(2-hydroxyethyl)pyrrolidin-1-yl)propoxy-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (377 mg, 43% yield): ¹H-NMR (DMSO-d₆): 10.40 (s, 1H), 8.60 (s, 1H),    8.05 (s, 1H), 7.55-7.65 (m, 1H), 7.30-7.40 (m, 3H), 7.20 (s, 1H),    6.80-6.90 (m, 1H), 4.20 (t, 2H) 3.95 (s, 3H), 3.80 (s, 2H),    3.30-3.50 (m, 2H), 3.00-3.10 (m, 1H), 2.90-3.00 (m, 1H), 2.30-2.40    (m, 1H), 2.10-2.20 (m, 1H), 2.05 (m, 1H), 1.80-1.90 (m, 2H), 1.67    (m, 1H), 1.63 (m, 2H), 1.20-1.40 (m, 2H):

MS (+ve ESI): 581 (M+H)⁺

MS (−ve ESI): 579 (M+H)⁻

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-((2S)-2-(2-hydroxyethyl)pyrrolidin-1-yl)propoxy-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (142 mg, 0.245 mmol) yielded di(tert-butyl)    2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethyl    phosphate (110 mg, 58% yield):

¹H-NMR (DMSO-d₆): 12.00 (s, 1H), 10.40 (s, 1H), 8.70 (s, 1H), 8.10 (s,1H), 7.72 (m, 1H), 7.40 (s, 1H), 7.33 (m, 2H), 7.20 (s, 1H), 6.92 (m,1H), 4.20 (t, 2H), 3.90 (s, 3H), 3.90 (s, 2H), 3.82 (m, 1H), 3.10-3.20(m, 1H), 2.90-3.00 (m, 1H), 2.44 (m, 1H), 2.20-2.30 (m, 1H), 2.00-2.15(m, 1H), 1.80-2.00 (m, 4H), 1.60-1.70 (m, 2H), 1.40-1.50 (m, 1H), 1.35(s, 18H), 0.80-0.90 (m, 2H):

MS (+ve ESI): 331 (N+H-^(t)Butyl)⁺/2

EXAMPLE 17 Preparation of Compound 17 in Table1—2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropylphosphate (185 mg, 0.248 mmol) yielded the title compound (145 mg, 83%yield):

¹H-NMR (DMSO-d₆): 10.80 (s, 1H), 9.20 (br s, 1H), 9.00 (s, 1H), 7.80 (s,1H), 7.60-7.70 (m, 2H), 7.45 (s, 1H), 7.30-7.40 (m, 2H), 6.80-6.90 (m,1H), 4.30 (t, 2H), 4.01 (s, 2H), 3.95 (s, 3H), 3.88 (m, 2H), 3.00-3.20(m, 2H), 2.30-2.40 (m, 2H), 1.40 (s, 6H):

MS (+ve ESI): 635 (M+H)⁺

di(tert-butyl)2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with 2-amino-2-methylpropanol (888 mg, 10 mmol) yielded    N-(3-fluorophenyl)-2-(2-((7-(3-((1-hydroxy-2-methylprop-2-yl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (306 mg, 28% yield):

¹H-NMR (DMSO-d₆): 10.45 (s, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 7.62 (m,1H), 7.40 (s, 1H), 7.25-7.35 (m, 2H), 7.20 (s, 1H), 6.80-6.90 (m, 1H),4.20 (t, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.20 (s, 2H), 2.70 (t, 2H),1.80-1.95 (m, 2H), 1.00 (s, 6H):

MS (+ve ESI): 555 (M+H)⁺

MS (−ve ESI): 553 (M+H)⁻

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-((1-hydroxy-2-methylprop-2-yl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (306 mg, 0.55 mmol) yielded di(tert-butyl)    2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    phosphate (185 mg, 45% yield):

¹H-NMR (DMSO-d₆): 10.50 (s, 1H), 8.70 (s, 1H), 8.20 (s, 1H), 7.80-7.90(m, 1H), 7.30-7.40 (m, 3H), 7.20 (s, 1H), 6.93 (m, 1H), 4.20 (t, 2H),3.90 (s, 3H), 3.70 (d, 2H), 2.70-2.75 (m, 2H), 1.92 (m, 2H), 1.40 (s,18H), 1.05 (t, 6H):

MS (+ve ESI): 747 (M+H)⁺

EXAMPLE 18 Preparation of Compound 18 in Table1—((2R)-1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)((2R)-1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (228 mg, 0.294 mmol) yielded the title compound (185 mg, 85%yield):

¹H-NMR (DMSO d₆): 9.05 (s, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 7.64 (s,1H), 7.52 (t, 1H), 7.41 (s, 1H), 7.37 (t, 1H), 7.15 (d, 1H), 4.32 (m,2H), 4.21 (m, 2H), 3.79 (m, 1H), 3.70 (m, 1H), 3.31 (m, 1H), 3.23 (m,1H), 2.34 (m, 2H), 2.20 (m, 1H), 2.06 (m, 1H), 1.96 (m, 1H), 1.82 (m,1H):

MS (+ve ESI): 663.5 (M+H)⁺.

di(tert-butyl)((2R)-1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) Triethylamine (26.7 ml, 0.192 mol) and triphenylmethyl chloride    (52.0 g, 0.187 mol) were added to a suspension of methyl    (2-amino-1,3-thiazol-5-yl)acetate (30.0 g, 0.174 mol—for method see    example 1l) in dichloromethane (450 ml) at 0° C. The reaction    mixture was stirred for 15 minutes and then allowed to warm to    ambient temperature over 3 hours before solvent evaporation in    vacuo. Water (300 ml) was added and the aqueous phase was extracted    with ethyl acetate. The organic phase was washed with brine, dried    over magnesium sulphate, and concentrated under reduced pressure to    yield methyl (2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetate    (64.1 g, 89% yield) as a white solid:

¹H-NMR (DMSO d₆): 8.41 (s, 1H), 7.18-7.37 (m, 15H), 6.60 (s, 1H), 3.61(m, 5H):

MS (−ve ESI): 413 (M−H)⁻.

-   b) Sodium hydroxide (300 ml of a 1.0 N solution in water) was added    to a solution of methyl    (2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetate (80.9 g,    0.195 mol) in ethanol (600 ml) at 0° C. Tetrahydrofuran (200 ml) was    added and the reaction was allowed to warm to ambient temperature    over 3 hours before solvent evaporation in vacuo. The residue was    acidified with aqueous hydrochloric acid (6.0 N) to pH 2 and the    product collected by suction filtration to yield    (2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetic acid (70.0 g,    88% yield) as a white solid:

¹H-NMR (DMSO d₆): 8.41 (s, 1H), 7.18-7.37 (m, 15H), 6.58 (s, 1H), 3.60(s, 2H):

MS (−ve ESI): 399 (M−H)⁻.

-   c) A solution of    (2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetic acid (8.0 g,    20 mmol), 3-chloroaniline (3.30 g, 26 mmol) and    diisopropylethylamine (4.5 ml, 26 mmol) in dimethylformamide (50 ml)    under inert and anhydrous conditions, was treated portionwise with    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluoro-phosphate (9.88 g, 26 mmol) at 50° C. for 19 hours. The    reaction was cooled to ambient temperature and poured into aqueous    sodium bicarbonate solution. A small amount of methanol was added to    resolubilise the brown solid and then iced water was added to    precipitate the product. Drying in vacuo yielded    N-(3-chlorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    as a beige solid (8.63 g, 65% yield):

¹H-NMR (DMSO d₆): 10.24 (br s, 1H), 8.49 (br s, 1H), 7.74 (s, 1H),7.08-7.39 (m, 18H), 6.61 (s, 1H), 3.56 (s, 2H):

MS (+ve ESI): 510 (M+H)⁺.

-   d) A mixture of    N-(3-chlorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (8.50 g, 16.7 mmol) and    N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (4.46 g, 16.7 mmol) were heated in acetic acid (75 ml) at 140° C.    for 7 hours. The reaction mixture was evaporated to dryness, the    residue was triturated with diethyl ether and the yellow solid    collected by suction filtration and washed with diethyl ether.    Extended drying in vacuo yielded    N-(3-chlorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (6.63 g, 77% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.01 (br s, 1H), 10.42 (br s, 1H), 8.65 (s, 1H), 8.05(s, 1H), 7.80 (s, 1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.25 (s, 1H), 7.05(d, 1H), 4.25 (t, 2H), 3.98 (s, 3H), 3.85 (s, 2H), 3.80 (t, 2H), 2.25(m, 2H):

MS (+ve ESI): 518, 520 (M+H)⁺

MS (−ve ESI): 516, 518 (M−H)⁻.

-   e) An analogous reaction to that described in example 1h, but    starting with (R)-(−)-2-pyrrolidinylmethanol (334 mg, 3.3 mmol)    yielded    N-(3-chlorophenyl)-2-(2-((7-(3-((2R)-2-hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (76 mg, 59% yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.90 (s, 1H), 7.85 (t, 1H), 7.63(s, 1H), 7.46 (dd, 1H), 7.35 (t, 1H), 7.29 (s, 1H), 7.13 (dd, 1H), 4.29(t, 2H), 3.99 (s, 2H), 3.98 (s, 3H), 3.76 (m, 1H), 3.62 (m, 4H), 3.21(m, 2H), 2.29 (m, 2H), 2.40 (m, 1H), 2.02 (m, 1H), 1.89 (m, 1H), 1.77(m, 1H):

MS (+ve ESI): 583 (M+H)⁺.

-   f) An analogous reaction to that described in example 1i but    starting with    N-(3-chlorophenyl)-2-(2-((7-(3-((2R)-2-hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin)amino)-1,3-thiazol-5-yl)acetamide    (600 mg, 1.01 mmol) yielded di(tert-butyl)    ((2R)-1-(3-((4-((5-2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (228 mg, 29% yield):

¹H-NMR (DMSO d₆): 8.67 (s, 1H), 8.11 (s, 1H), 7.86 (m, 1H), 7.48 (d,1H), 7.37 (m, 2H), 7.25 (s, 1H), 7.14 (d, 1H), 4.21 (m, 2H), 3.97 (s,3H), 3.89 (s, 2H), 3.78 (m, 1H), 3.57 (m, 1H), 3.09 (m, 1H), 2.98 (m,1H), 2.68 (m, 1H), 2.46 (m, 1H), 2.22 (q, 1H), 1.98 (m, 2H), 1.88 (m,1H), 1.70 (m, 2H), 1.62 (m, 1H), 1.37 (s, 18H):

MS (+ve ESI): 775.6 (M+H)⁺.

EXAMPLE 19 Preparation of Compound 19 in Table1—2-(1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 1 but starting withdi(tert-butyl)-2-(1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethylphosphate (153 mg, 0.19 mmol) yielded the title compound (136 mg, 94%yield):

¹H-NMR (DMSO d₆): 10.92 (br s, 1H), 9.00 (s, 1H), 7.90 (s, 1H), 7.80 (s,1H), 7.65 (d, 2H), 7.60 (s, 1H), 7.40 (s, 1H), 7.33 (m, 1H), 7.10 (d,1H), 4.20-4.40 (m, 2H), 4.00 (s, 2H), 3.95 (s, 3H), 3.85 (m, 2H), 3.32(m, 1H), 3.17 (m, 1H), 2.95 (m, 2H), 2.30 (m, 2H), 1.85 (m, 2H), 1.65(m, 2H), 1.52 (m, 2H):

MS (+ve ESI): 691, 693 (M+H)⁺.

di(tert-butyl)-2-(1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 18e, but    starting with 4-(2-hydroxyethyl)piperidine (426 mg, 3.3 mmol)    yielded    N-(3-chlorophenyl)-2-(2-((7-(3-(4-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (78 mg, 58% yield):

¹H-NMR (DMSO d₆): 10.42 (br s, 1H), 8.65 (s, 1H), 7.80 (s, 1H), 7.47 (m,1H), 7.33 (m, 2H), 7.22 (s, 1H), 7.11 (m, 1H), 4.28 (m, 1H), 4.17 (m,2H), 3.94 (s, 3H), 3.85 (s, 2H), 3.41 (m, 2H), 2.82 (m, 2H), 2.40 (m,2H), 1.92 (m, 4H), 1.60 (m, 2H), 1.36 (m, 3H), 1.16 (m, 2H):

MS (+ve ESI): 611 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3-chlorophenyl)-2-(2-((7-(3-(4-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (170 mg, 0.28 mmol) yielded    di(tert-butyl)-2-(1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyl    phosphate (153 mg, 69% yield):

¹H-NMR (DMSO d₆): 10.92 (br s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 7.80 (s,1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 4.20 (t,2H), 3.95 (s, 3H), 3.85 (m, 4H), 2.90 (m, 2H), 1.90 (m, 4H), 2.30 (m,2H), 1.65 (m, 2H), 1.48 (m, 2H), 1.40 (s, 18H), 1.17 (m, 2H);

MS (+ve ESI): 801, 803 (M+H)⁺.

EXAMPLE 20 Preparation of Compound 20 in Table1—2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethylphosphate (340 mg, 0.42 mmol) yielded the title compound (320 mg, 94%yield):

¹H-NMR (DMSO d₆, CD₃COOD): 9.03 (s, 1H), 7.88 (s, 1H), 7.61 (s, 1H),7.37 (m, 3H), 6.87 (m, 1H), 4.33 (m, 2H), 4.29 (m, 2H), 4.03 (s, 2H),3.99 (s, 3H), 3.67 (m, 8H), 3.50 (m, 2H), 3.41 (m, 2H), 2.37 (m, 2H):

MS (+ve ESI): 694.6 (M+H)⁺.

di(tert-butyl)2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 18c, but    starting with 3,5-difluoroaniline (2.09 g, 16.3 mmol) and    (2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetic acid (5.00 g,    12.5 mmol) yielded    N-(3,5-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (4.75 g, 74% yield):

¹H-NMR (DMSO d₆): 7.30 (m, 2H), 6.92 (m, 1H), 7.10 (m, 2H), 6.75 (br s,2H), 6.72 (s, 1H), 3.65 (s, 2H):

MS (+ve ESI): 511.9 (M+H)⁺.

-   b) A mixture of    N-(3,5-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (5.38 g, 20.0 mmol) and    N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (5.91 g, 20.0 mmol) were heated in acetic acid (50 ml) at 140° C.    for 4.5 hours. The reaction mixture was evaporated to dryness, the    residue was triturated with acetonitrile and the yellow solid    collected by suction filtration and washed with diethyl ether.    Extended drying in vacuo yielded    N-(3,5-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (5.88 g, 57% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.00 (br s, 1H), 10.59 (br s, 1H), 8.64 (s, 1H), 8.11(s, 1H), 7.38 (s, 1H), 7.34 (m, 2H), 7.26 (s, 1H), 6.89 (m, 1H), 4.25(t, 2H), 3.98 (s, 3H), 3.85 (s, 2H), 3.80 (t, 2H), 2.25 (m, 2H):

MS (+ve ESI): 520 (M+H)⁺

MS (−ve ESI): 518 (M−H)⁻.

-   c) An analogous reaction to that described in example 1h, but    starting with 1-(2-hydroxyethyl)piperazine (430 mg, 3.3 mmol) and    N-(3,5-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (114 mg, 0.22 mmol) yielded    N-(3,5-difluorophenyl)-2-(2-((7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (124 mg, 92% yield):

¹H-NMR (DMSO d₆, TFA): 10.63 (s, 1H), 8.66 (s, 1H), 8.10 (s, 1H), 7.38(s, 1H), 7.34 (dd, 2H), 7.23 (s, 1H), 6.43 (m, 1H), 4.35 (m, 1H), 4.18(t, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.48 (m, 2H), 2.70 (m, 1H), 2.40(m, 12H), 1.96 (m, 2H):

MS (+ve ESI): 614 (M+H)⁺

-   d) An analogous reaction to that described in example 1i, but    starting with    N-(3,5-difluorophenyl)-2-(2-((7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (460 mg; 0.75 mmol) yielded di(tert-butyl)    2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    phosphate (340 mg, 56% yield):

¹H-NMR: 8.67 (s, 1H), 8.11 (s, 1H), 7.39 (s, 1H), 7.35 (m, 2H), 7.24 (s,1H), 6.94 (m, 1H), 4.20 (t, 2H), 3.97 (s, 3H), 3.94 (m, 2H), 3.91 (s,2H), 2.55 (m, 4H), 2.45 (m, 8H), 1.97 (m, 2H), 1.42 (s, 18H):

EXAMPLE 21 Preparation of Compound 21 in Table1—2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethylphosphate (470 mg, 0.62 mmol) yielded the title compound (378 mg, 94%yield):

¹H-NMR (DMSO d₆): 9.06 (s, 1H), 7.88 (s, 1H), 7.64 (s, 1H), 7.43 (m,3H), 6.95 (m, 1H), 4.31 (m, 4H), 4.05 (s, 2H), 3.99 (s, 3H), 3.46 (m,2H), 3.34 (m, 2H), 2.88 (s, 3H), 2.33 (m, 2H):

MS (+ve ESI): 639.5 (M+H)⁺.

di(tert-butyl)2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 20c but    starting with 2-methylaminoethanol (248 mg, 3.3 mmol) yielded    N-(3,5-difluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (33 mg, 27% yield):

¹H-NMR (DMSO d₆): 12.04 (br s, 1H), 10.65 (s, 1H), 8.69 (s, 1H), 8.13(br s, 1H), 7.40 (s, 1H), 7.36 (dd, 2H), 7.27 (s, 1H), 6.95 (m, 1H),4.38 (m, 1H), 4.21 (t, 2H), 3.98 (s, 3H), 3.93 (s, 2H), 3.49 (m, 2H),2.48 (m, 2H), 2.45 (m, 2H), 2.24 (s, 3H), 1.95 (m, 2H):

MS (+ve ESI): 559 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3,5-difluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (500 mg, 0.896 mmol) yielded di(tert-butyl)    2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    phosphate (375 mg, 56% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.12 (s, 1H), 7.40 (s, 1H), 7.36 (m,2H), 7.24 (s, 1H), 6.94 (m, 1H), 4.21 (t, 2H), 3.97 (s, 3H), 3.92 (m,4H), 2.62 (t, 2H), 2.57 (t, 2H), 2.25 (s, 3H), 1.95 (m, 2H), 1.39 (s,18H):

MS (+ve ESI): 751.6 (M+H)⁺.

EXAMPLE 22 Preparation of Compound 22 in Table1—((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (500 mg, 0.644 mmol) yielded the title compound (402 mg, 82%yield):

¹H-NMR (DMSO d₆): 9.05 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.40, (m,3H), 6.95 (s, 1H), 4.31 (m, 2H), 4.23 (m, 2H), 4.05 (s, 2H), 3.99 (s,3H), 3.80 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.30 (m, 1H), 3.23 (q,1H), 2.35 (m, 2H), 2.20 (m, 1H), 2.04 (m, 1H), 1.97 (m, 1H), 1.83 (m,1H):

MS (+ve ESI): 665.5 (M+H)⁺.

di(tert-butyl)((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 20c but    starting with (S)-(+)-2-pyrrolidinylmethanol (334 mg, 3.3 mmol)    yielded    N-(3,5-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (58 mg, 45% yield):

¹H-NMR (DMSO d₆, TFA): 9.09 (s, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 7.35(dd, 2H), 7.30 (s, 1H), 6.91 (t, 1H), 4.30 (m, 2H), 4.01 (s, 2H), 3.99(s, 3H), 3.77 (dd, 1H), 3.62 (m, 4H), 3.33 (m, 2H), 2.30 (m, 2H), 2.13(m, 1H), 2.02 (m, 1H), 1.90 (m, 1H), 1.79 (m, 1H);

MS (+ve ESI): 585 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3,5-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (759 mg, 1.3 mmol) yielded di(tert-butyl)    ((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (500 mg, 50% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.12 (s, 1H), 7.39 (s, 1H), 7.35 (m,2H), 7.24 (s, 1H), 6.95 (m, 1H), 4.22 (m, 2H), 3.97 (s, 3H), 3.92 (s,2H), 3.80 (m, 1H), 3.61 (m, 1H), 3.12 (m, 1H), 3.00 (m, 1H), 2.72 (m,1H), 2.50 (m, 1H), 2.25 (q, 1H), 1.98 (m, 2H), 1.90 (m, 1H), 1.70 (m,2H), 1.63 (m, 1H), 1.37 (s, 18H):

MS (+ve ESI): 777.5 (M+H)⁺.

EXAMPLE 23 Preparation of Compound 23 in Table1—(1R)-2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-1-methylethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)(1R)-2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-1-methylethylphosphate (470 mg, 0.553 mmol) yielded the title compound (350 mg, 89%yield):

¹H-NMR (DMSO d₆, CD₃COOD): 9.00 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H),7.37 (m, 3H), 6.85 (m, 1H), 4.61 (m, 1H), 4.29 (m, 2H), 4.01 (s, 2H),3.96 (s, 3H), 3.20 (m, 4H), 2.28 (m, 2H), 1.32 (d, 3H):

MS (+ve ESI): 639.6 (M+H)⁺.

di(tert-butyl)(1R)-2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-1-methylethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 20c, but    starting with (R)-(−)-1-amino-2-propanol (248 mg, 3.3 mmol) yielded    N-(3,5-difluorophenyl)-2-(2-((7-(3-(((2R)-2-hydroxypropyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (40 mg, 32% yield):

¹H-NMR (DMSO d₆, TFA): 9.09 (s, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 7.34(dd, 2H), 7.28 (s, 1H), 6.90 (m, 1H), 4.29 (t, 1H), 4.01 (s, 3H), 3.99(s, 3H), 3.95 (m, 1H), 3.15 (t, 2H), 3.06 (dd, 1H), 2.83 (dd, 1H), 2.24(m, 2H), 1.15 (d, 3H):

MS (+ve ESI): 559 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3,5-difluorophenyl)-2-(2-((7-(3-(((2R)-2-hydroxypropyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (470 mg, 0.714 mmol) yielded di(tert-butyl)    (1R)-2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-1-methylethyl    phosphate (470 mg, 77% yield):

¹H-NMR (DMSO d₆): 8.68 (s, 1H), 8.12 (s, 1H), 7.40 (s, 1H), 7.35 (m, 2H)7.25 (s, 1H); 6.95 (m, 1H), 4.50 (m, 1H), 4.17 (m, 2H), 3.96 (s, 3H),3.91 (s, 2H), 2.32 (m, 2H), 2.05 (m, 2H), 1.42 (s, 18H), 1.22 (d, 3H).

EXAMPLE 24 Preparation of Compound 24 in Table1—((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

Di(tert-butyl)((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (450 mg, 0.58 mmol) in dioxane (20 ml) was treated with asolution of HCl (4N) in dioxane (940 μl) at ambient temperature for 15hours. The solid was recovered by filtration, washed with dioxane, driedin vacuo at 50° C. to yield the title compound (270 mg, 63% yield):

¹H-NMR (DMSO d₆, CD₃COOD): 9.07 (s, 1H), 7.90 (s, 1H), 7.80 (m, 1H),7.62 (s, 1H), 7.35 (m, 3H), 7.30 (s, 1H), 4.29 (t, 2H), 4.21 (m, 1H),4.14 (m, 1H), 3.97 (s, 5H), 3.82 (m, 1H), 3.70 (m, 1H), 3.58 (m, 1H),3.27 (m, 2H), 2.30 (m, 3H), 2.20 (m, 1H), 1.89 (m, 2H):

MS (+ve ESI): 665 (M+H)⁺.

Di(tert-butyl)((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 18c, but    starting with (2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetic    acid (10.0 g, 25.0 mmol) and 3,4-difluoroaniline (3.0 ml, 30 mol)    yielded    N-(3,4-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (9.61 g, 75% yield):

¹H-NMR (DMSO d₆): 8.36 (s, 1H), 7.70 (m, 1H), 7.13-7.37 (m, 17H), 6.58(s, 1H), 3.53 (s, 2H):

MS (−ve ESI): 510 (M−H)⁻.

-   b) A mixture of    N-(3,4-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (9.51 g, 18.6 mmol) and    N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (5.50 g, 18.6 mmol) were heated in acetic acid (50 ml) at 140° C.    for 5.5 hours. The reaction was allowed to stir at ambient    temperature for 16 hours, the yellow solid was collected by suction    filtration and was then washed with i) acetic acid, ii) acetonitrile    and iii) diethyl ether. Extended drying in vacuo yielded    N-(3,4-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (5.81 g, 60% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 10.42 (br s, 1H), 8.63 (s, 1H), 8.11 (s, 1H), 7.79 (m,1H), 7.32-7.41 (m, 4H), 4.25 (t, 2H), 3.98 (s, 3H), 3.85 (s, 2H), 3.79(t, 2H), 2.25 (m, 2H):

MS (+ve ESI): 520 (M+H)⁺

MS (−ve ESI): 518 (M−H)⁻.

-   c) An analogous reaction to that described in example 1h, but    starting with    N-(3,4-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    and (R)-(−)-2-pyrrolidinylmethanol (334 mg, 3.3 mmol) yielded    N-(3,4-difluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (90 mg, 70% yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.64(s, 1H), 7.39 (dd, 1H), 7.32 (m, 1H), 7.30 (s, 1H), 4.29 (t, 2H), 3.98(s, 5H), 3.77 (m, 1H), 3.62 (m, 4H), 3.21 (m, 2H), 2.29 (m, 2H), 2.11(m, 1H), 2.03 (m, 1H), 1.91 (m, 1H), 1.79 (m, 1H):

MS (+ve ESI): 585 (M+H)⁺.

-   d)    N-(3,4-difluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (600 mg, 1.02 mmol) was dissolved in dimethylacetamide (3 ml).    Tetrazole (144 mg, 2.05 mmol) and    di-tert-butyl-diethylphosphoramidite (571 μl, 2.05 mmol) were added    to the mixture, which was stirred at ambient temperature under argon    for 20 hours. The mixture was then diluted with dichloromethane    (60 ml) and washed with a saturated solution of sodium bicarbonate    (25 ml). The organic phase was recovered, dried over magnesium    sulphate, filtered and concentrated in vacuo. The crude product was    dissolved in tetrahydrofuran (15 ml) at 0° C., hydrogen peroxide    (30%, 210 μl) was added to the solution which was stirred for two    hours, warming from 0° C. to ambient temperature. The mixture was    then cooled to 0° C., sodium metabisulfite (390 mg, 2.05 mmol) was    added, the mixture was stirred at 0° C. for 15 minutes, diluted with    ethyl acetate, washed with a saturated solution of sodium    bicarbonate, the organic phase was recovered, dried over magnesium    sulphate, filtered, concentrated. The crude product was purified by    chromatography on silica gel, eluting with dichloromethane:7.0N    methanolic ammonia (2-5%), to yield di(tert-butyl)    ((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (490 mg, 61% yield):

¹H-NMR (DMSO d₆): 8.67 (s, 1H), 8.11 (s, 1H), 7.82 (m, 1H), 7.42 (m,1H), 7.40 (s, 1H), 7.33 (m, 1H), 7.25 (s, 1H), 4.22 (m, 2H), 3.97 (s,3H), 3.89 (s, 2H), 3.78 (m, 1H), 3.57 (m, 1H), 3.10 (m, 1H), 2.96 (m,1H), 2.68 (m, 1H), 2.46 (m, 1H), 2.22 (q, 1H), 1.97 (m, 2H), 1.88 (m,1H), 1.70 (m, 2H), 1.62 (m, 1H), 1.37 (s, 18H):

MS (+ve ESI): 777.7 (M+H)⁺.

EXAMPLE 25 Preparation of Compound 25 in Table1—((2S)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

Di(tert-butyl)((2S)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (537 mg, 0.69 mmol) in dioxane (10 ml) was treated with asolution of HCl (4N) in dioxane (1.2 ml) at ambient temperature for 15hours. The solid was recovered by filtration, washed with dioxane, driedunder vacuum at 50° C. to give the title compound (413 mg, 81% yield):

¹H-NMR (DMSO d₆, CD₃COOD): 9.07 (s, 1H), 7.90 (s, 1H), 7.80 (m, 1H),7.62 (s, 1H), 7.35 (m, 3H), 7.30 (s, 1H), 4.29 (t, 2H), 4.21 (m, 1H),4.14 (m, 1H), 3.97 (s, 5H), 3.82 (m, 1H), 3.70 (m, 1H), 3.58 (m, 1H),3.27 (m, 2H), 2.30 (m, 3H), 2.20 (m, 1H), 1.89 (m, 2H);

MS (+ve ESI): 665 (M+H)⁺.

Di(tert-butyl)((2S)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 24c, but    starting with (S)-(+)-2-pyrrolidinylmethanol (1.42 ml, 14.5 mmol)    yielded    N-(3,4-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (825 mg, 49% yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.64(s, 1H), 7.39 (dd, 1H), 7.32 (m, 1H), 7.30 (s, 1H), 4.29 (t, 2H), 3.98(s, 5H), 3.77 (m, 1H), 3.62 (m, 4H), 3.21 (m, 2H), 2.29 (m, 2H), 2.11(m, 1H), 2.03 (m, 1H), 1.91 (m, 1H), 1.79 (m, 1H):

MS (+ve ESI): 585 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3,4-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (794 mg, 1.36 mmol) yielded di(tert-butyl)    ((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (537 mg, 51% yield):

¹H-NMR (DMSO d₆): 8.67 (s, 1H), 8.11 (s, 1H), 7.82 (m, 1H), 7.42 (m,1H), 7.40 (s, 1H), 7.33 (m, 1H), 7.25 (s, 1H), 4.22 (m, 2H), 3.97 (s,3H), 3.89 (s, 2H), 3.78 (m, 1H), 3.57 (m, 1H), 3.10 (m, 1H), 2.96 (m,1H), 2.68 (m, 1H), 2.46 (m, 1H), 2.22 (q, 1H), 1.97 (m, 2H), 1.88 (m,1H), 1.70 (m, 2H), 1.62 (m, 1H), 1.37 (s, 18H):

MS (+ve ESI): 777 (M+H)⁺.

EXAMPLE 26 Preparation of Compound 26 in Table1—1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)(1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate (321 mg, 0.41 mmol) yielded the title compound (258 mg, 85%yield):

¹H-NMR (DMSO d₆): 11.20 (s, 1H), 10.70 (s, 1H), 8.97 (s, 1H), 7.84 (m,1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.43 (m, 3H), 4.30 (m, 2H), 4.04 (s,2H), 3.95 (s, 3H), 3.70 (t, 2H), 3.56 (m, 2H), 3.50-3.40 (m, 2H), 3.23(m, 2H), 2.98 (m, 2H), 2.37 (m, 2H), 1.90 (m, 3H), 1.65 (m, 2H):

MS (+ve ESI): 679 (M+H)⁺.

di(tert-butyl)(1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with    N-(3,4-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.50 g, 2.89 mmol) and piperidin-4-ylmethanol (1.66 g, 14.4 mmol)    yielded    N-(3,4-difluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (989 mg, 57% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO-d₆): 12.00 (s, 1H), 10.45 (s, 1H), 8.70 (s, 1H), 8.15 (s,1H), 7.65-7.75 (m, 1H), 7.40-7.50 (m, 3H), 7.25 (s, 1H), 4.40 (br s,1H), 4.20 (t, 2H), 3.98 (s, 3H), 3.90 (s, 2H), 3.22 (m, 2H), 2.80-2.90(m, 2H), 2.50 (t, 2H), 1.80-2.00 (m, 4H), 1.50-1.60 (m, 2H), 1.32 (m,1H), 1.12 (m, 2H):

MS (+ve ESI): 599 (M+H)⁺

MS (−ve ESI): 597(M−H)⁻.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(3,4-difluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (963 mg, 1.61 mmol) yielded di(tert-butyl)    (1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    phosphate (343 mg, 34% yield):

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.45 (s, 1H), 8.65 (s, 1H), 8.20 (s,1H), 7.67 (m, 1H), 7.25-7.45 (m, 3H), 7.25 (s, 1H), 4.20 (t, 2H), 3.95(s, 3H), 3.90 (s, 2H), 3.74 (m, 1H), 2.80-2.90 (m, 1H), 2.40-2.50 (m,2H), 1.80-2.00 (m, 4H), 1.60-1.70 (m, 3H), 1.40 (s, 18H), 1.18 (m, 2H):

MS (+ve ESI): 791 (M+H)⁺.

EXAMPLE 27 Preparation of Compound 27 in Table1—(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyldihydrogen phosphate

Hydrochloric acid (1 ml of a 4.0 N solution in 1,4-dioxane, 4 mmol) wasadded, dropwise to a solution of di(tert-butyl)(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate (assumed 379 mg, 0.49 mmol) in 1,4-dioxane (15 ml) upon whicha light yellow solid precipitated from the reaction mixture. Theresulting heterogeneous reaction mixture was stirred for a further 20hours and the precipitate was filtered and washed with 1,4-dioxane (2×5ml) then dried under high vacuum for 48 hours to furnish(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyldihydrogen phosphate bis-hydrochloride as a light yellow solid (302 mg,84% yield):

¹H-NMR (DMSO d₆): 10.52 (m, 1H), 10.19 (s, 1H), 9.02 (s, 1H), 7.83 (m,2H), 7.58 (s, 1H), 7.42 (s, 1H), 7.24 (m, 1H), 7.17 (m, 2H), 4.27 (t,2H), 4.05 (s, 2H), 3.95 (s, 3H), 3.70 (t, 2H), 3.53 (m, 2H), 3.20 (m,2H), 2.93 (q, 2H), 2.34 (m, 2H), 2.86 (br d, 3H), 1.60 (m, 1H):

MS (+ve ESI): 661 (M+H)⁺.

di(tert-butyl)(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1p, but    starting with 2-((tert-butoxycarbonyl)amino)-1,3-thiazol-5-yl)acetic    acid (1.50 g, 5.81 mmol) and 2-fluoroaniline (0.73 ml, 7.56 mol)    yielded tert-butyl    5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-ylcarbamate    (1.25 g, 61% yield):

MS (+ve ESI): 352 (M+H)⁺.

-   b) A mixture of tert-butyl    5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-ylcarbamate    (9.88 g, 20.0 mmol) and    N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (5.91 g, 20.0 mmol) were heated in acetic acid (75 ml) at 140° C.    for 4 hours. The reaction mixture was cooled to ambient temperature,    the yellow solid was collected by suction filtration and washed    with i) acetic acid, ii) acetontrile and iii) diethyl ether.    Extended drying in vacuo yielded    N-(2-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (7.57 g, 76% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 10.00 (br s, 1H), 8.63 (s, 1H), 8.11 (s, 1H), 7.88 (m,1H), 7.38 (s, 1H), 7.25 (m, 2H), 7.16 (m, 2H), 4.25 (t, 2H), 3.95 (m,5H), 3.80 (t, 2H), 2.25 (m, 2H):

MS (+ve ESI): 502 (M+H)⁺

MS (−ve ESI): 500 (M−H)⁻.

-   c) An analogous reaction to that described in example 1h, but    starting with    N-(2-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (0.50 g, 1.0 mmol) and piperidin-4-ylmethanol (0.60 ml, 5.0 mmol)    yielded    N-(2-fluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (325 mg, 55% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO d₆): 9.98 (br s, 1H), 8.63 (s, 1H), 8.06 (s, 1H), 7.88 (m,1H), 7.37 (s, 1H), 7.25 (m, 1H), 7.21 (s, 1H), 7.15 (m, 2H), 4.32 (m,1H), 4.17 (t, 2H), 3.93 (s, 3H), 3.12 (m, 2H), 2.89 (m, 2H), 2.40 (m,2H), 1.81-1.96 (m, 4H), 1.60 (m, 2H), 1.30 (m, 1H), 1.10 (m, 2H):

MS (+ve ESI): 581 (M+H)⁺.

-   d)    N-(2-fluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (285 mg, 0.49 mmol) and dry 1H-tetrazole (104 mg, 1.47 mmol) were    dissolved in dry dimethylacetamide (10 ml) under a nitrogen    atmosphere. Di-tert-butyl diethylphosphoramidite (210 μl, 0.74 mmol)    was added, in one portion, to the stirred homogeneous reaction    mixture and left to stir at ambient temperature for 2 hours upon    which time the reaction mixture was diluted with dichloromethane    (20 ml) and washed with sodium hydrogen carbonate (20 ml of a    saturated aqueous solution). The aqueous layer was further extracted    with dichloromethane (3×20 ml) and the combined organic layers were    dried over sodium sulphate, filtered and concentrated under reduced    pressure to yield a viscous, yellow oil which was used promptly in    the next step of the reaction sequence without further purification:

MS (+ve ESI): 701 (M+H-tBu)⁺.

Hydrogen peroxide (120 μl of a 30% w/w aqueous solution, 0.98 mmol) wasadded dropwise to a stirred and cooled (0° C.) solution of the crudephosphite in tetrahydrofuran (5 ml) and warmed to ambient temperatureover 10 minutes. The resulting homogeneous solution was stirred for 2hours upon which time the reaction was then cooled (0° C.) and asolution of sodium thiosulphite (3 ml of a 0.53 N aqueous solution) wasintroduced, dropwise. The reaction was warmed to ambient temperatureover 10 minutes then diluted with ethyl acetate (20 ml) and sodiumhydrogen carbonate (20 ml of a saturated aqueous solution), the phasesseparated and the aqueous layer further extracted with ethyl acetate(2×20 ml). The combined organic layers were dried over sodium sulphate,filtered and concentrated under reduced pressure to furnishdi(tert-butyl)(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate as a viscous, yellow oil which was used in the next step ofthe reaction sequence without further, purification (assumed 379 mg,quantitative yield):

MS (+ve ESI): 773 (M+H)⁺.

EXAMPLE 28 Preparation of Compound 28 in Table1—((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

Di(tert-butyl)((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (310 mg, 0.41 mmol) in 1,4-dioxane (25 ml) was treated with4.0 N hydrochloric acid in 1,4-dioxane (0.7 ml, 2.86 mmol) at 20° C. for18 hours. The solid product was collected by suction filtration andwashed successively with 1,4-dioxane (50 ml), acetonitrile (50 ml) thendiethyl ether (50 ml), dried in vacuo to give the title compound (287mg, 97% yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.08 (s, 1H), 8.90 (s, 1H), 7.80 (m, 2H), 7.50 (s,1H), 7.35 (s, 1H), 7.18 (m, 1H), 7.07 (m, 2H), 4.22 (m, 2H), 4.12 (m,2H), 3.95 (s, 2H), 3.90 (s, 3H), 3.70 (m, 1H), 3.59 (m, 1H), 3.48 (m,1H), 3.20 (m, 1H), 3.10 (m, 1H), 2.21 (m, 2H), 2.10 (m, 1H), 1.95 (m,1H), 1.85 (m, 1H), 1.72 (m, 1H):

MS (+ve ESI): 647 (M+H)⁺.

MS (−ve ESI): 645 (M−H)⁻.

di(tert-butyl)((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate, used as the starting material was obtained as follows:

-   a)    N-(2-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (884 mg, 1.5 mmol) in dimethylacetamide (5 ml) was reacted with    2(R)-pyrrolidinylmethanol (D-prolinol) (307 mg, 3.0 mmol) in the    presence of tetrabutylammonium iodide (100 mg) at 60° C., under an    inert atmosphere, for 6 hours. The cooled reaction solution was    purified by chromatography on silica gel, eluting with    dichloromethane:7.0N methanolic ammonia (2-8%); evaporation of    solvent and drying in vacuo yielded    N-(2-fluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (583 mg, 69% yield) as an orange solid:

¹H-NMR (DMSO d₆): 10.01 (s, 1H), 8.66 (s, 1H), 8.10 (s, 1H), 7.90 (m,1H), 7.37 (s, 1H), 7.25 (m, 1H), 7.23 (s, 1H), 7.15 (m, 2H), 4.29 (br s,1H), 4.20 (t, 2H), 3.95 (s, 2H), 3.95 (s, 3H), 3.39 (m, 1H), 3.20 (m,1H), 3.05 (m, 1H), 2.95 (m, 1H), 2.42 (m, 2H), 2.15 (m, 1H), 1.49-1.98(m, 6H):

MS (+ve ESI): 567 (M+H)⁺.

MS (−ve ESI): 565 (M−H)⁻.

-   b)    N-(2-fluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (427 mg, 0.75 mmol) in dimethyl acetamide (4 ml) was treated with    tetrazole (105 mg, 1.5 mmol) and    di-tert-butyl-diethylphosphoramidite (493 mg, 1.84 mmol) at 20° C.,    under an inert atmosphere, for 3 hours. The reaction solution was    cooled to −10° C. and 30% hydrogen peroxide solution (0.22 ml, 1.84    mmol) was added dropwise over 5 minutes. After stirring for 2 hours    at 20° C. the reaction was quenched at −10° C. with 0.5N sodium    thiosulphate solution. The mixture was extracted twice with ethyl    acetate (20 ml) and the organic solution dried over magnesium    sulphate, evaporated and the resulting oil purified by    chromatography on silica gel, eluting with dichloromethane:7.0 N    methanolic ammonia (0-4%). Evaporation of solvent and drying in    vacuo yielded di(tert-butyl)    ((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (310 mg, 55% yield) as a yellow gum:

MS (+ve ESI): 759 (M+H)⁺.

MS (−ve ESI): 757 (M−H)⁻.

EXAMPLE 29 Preparation of Compound 29 in Table1—((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 28 but starting withdi(tert-butyl)((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (612 mg, 0.81 mmol) yielded the title compound (527 mg, 86%yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.29 (s, 1H), 9.00 (s, 1H), 7.85 (m, 1H), 7.80 (s,1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.28 (m, 1H), 7.18 (m, 2H), 4.30 (m,3H), 4.20 (m, 1H), 4.05 (s, 2H), 3.95 (s, 3H), 3.80 (m, 1H), 3.65 (m,1H), 3.60 (m, 1H), 3.28 (m, 1H), 3.20 (m, 1H), 2.25 (m, 2H), 2.20 (m,1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.80 (m, 1H):

MS (+ve ESI): 647 (M+H)⁺.

MS (−ve ESI): 645 (M−H)⁻.

di(tert-butyl)((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28a, but    starting with 2-(S)-pyrrolidinylmethanol (L-prolinol) (615 mg, 6.0    mmol) and    N-(2-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.12 g, 2.0 mmol). Purification by reverse phase HPLC eluting with    40% acetonitrile in water containing 0.1% TFA and basification of    the product fractions with ammonia. After concentration to low    volume the solid product was collected by suction filtration, washed    with water and dried in vacuo to yield    N-(2-fluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (697 mg, 62% yield):

¹H-NMR (DMSO d₆): 11.95 (br s, 1H), 9.95 (s, 1H), 8.57 (s, 1H), 8.00 (s,1H), 7.85 (m, 1H), 7.29 (s, 1H), 7.20 (m, 1H), 7.15 (s, 1H), 7.08 (m,2H), 4.25 (br s, 1H), 4.10 (t, 2H), 3.85 (s, 2H), 3.85 (s, 3H), 3.30 (m,1H), 3.10 (m, 1H), 3.00 (m, 1H), 2.85 (m, 1H), 2.30 (m, 2H), 2.08 (m,1H), 1.40-1.90 (m, 6H):

MS (+ve ESI): 567 (M+H)⁺.

MS (−ve ESI): 565 (M−H)⁻.

-   b) An analogous reaction to that described in example 28b, but    starting with    N-(2-fluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (600 mg, 1.06 mmol) yielded di(tert-butyl)    ((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (625 mg, 78% yield) as a yellow gum:

¹H-NMR (DMSO d₆): 10.08 (s, 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.92 (m,1H), 7.37 (s, 1H), 7.25 (m, 1H), 7.22 (s, 1H), 7.18 (m, 2H), 4.20 (m,2H), 3.95 (s, 2H), 3.95 (s, 3H), 3.78 (m, 1H), 3.55 (m, 1H), 3.10 (m,1H), 2.95 (m, 1H), 2.68 (m, 1H), 2.47 (m, 1H), 2.20 (m, 1H), 1.80-2.00(m, 3H), 1.50-1.70 (m, 3H), 1.35 (s, 18H):

MS (+ve ESI): 759 (M+H)⁺.

MS (−ve ESI): 757 (M−H)⁻.

EXAMPLE 30 Preparation of Compound 30 in Table1—2-(ethyl(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 28 but starting withdi(tert-butyl)2-(ethyl(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethylphosphate (888 mg, 1.19 mmol) yielded the title compound (544 mg, 61%yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.80 (br s, 1H), 10.17 (s, 1H), 8.95 (s, 1H), 7.78(m, 2H), 7.50 (s, 1H), 7.38 (s, 1H), 7.20 (m, 1H), 7.09 (m, 2H), 4.20(m, 4H), 4.00 (s, 2H), 3.90 (s, 3H), 3.35 (m, 2H), 3.22 (m, 4H), 2.24(m, 2H), 1.20 (t, 3H):

MS (+ve ESI): 635 (M+H)⁺

MS (−ve ESI): 633 (M−H)⁻.

di(tert-butyl)2-(ethyl(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28a, but    starting with 2-ethylaminoethanol (802 mg, 9.0 mmol) and    N-(2-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.68 g, 3.0 mmol), and purifying the product by reverse phase HPLC    eluting with 40% acetonitrile in water containing 0.1% TFA, yielded    2-(2-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(2-fluorophenyl)acetamide    (972 mg, 58% yield):

¹H-NMR (DMSO d₆): 9.89 (s, 1H), 8.37 (s, 1H), 7.92 (m, 1H), 7.85 (s,1H), 7.25 (m, 1H), 7.15 (m, 3H), 7.00 (s, 1H), 4.35 (br s, 1H), 4.10 (t,2H), 3.90 (s, 3H), 3.82 (s, 2H), 3.40 (t, 2H), 2.60 (m, 2H), 2.47 (m,2H), 1.88 (m, 2H), 0.95 (t, 3H):

MS (+ve ESI): 555 (M+H)⁺

MS (−ve ESI): 553 (M−H)⁻.

-   b) An analogous reaction to that described in example 28b, but    starting with    2-(2-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(2-fluorophenyl)acetamide    (1.15 g, 1.7 mmol) yielded di(tert-butyl)    2-(ethyl(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    phosphate (888 mg, 70% yield) as a yellow oil:

MS (+ve ESI): 747 (M+H)⁺

MS (−ve ESI): 745 (M−H)⁻.

EXAMPLE 31 Preparation of Compound 31 in Table1—2-(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 28, but starting withdi(tert-butyl)2-(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethylphosphate (484 mg, 0.615 mmol) and the resulting yellow solid waspurified by silica chromatography, eluting with 100:40:8:8dichloromethane:methanol:water:formic acid, evaporation of solvent anddrying in vacuo yielded the title compound (300 mg, 62% yield) as ayellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.10 (s, 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.90 (m,1H), 7.38 (s, 1H), 7.25 (m, 2H), 7.17 (m, 2H), 4.20 (m, 2H), 4.00 (s,3H), 3.99 (s, 2H), 3.76 (m, 1H), 3.10 (m, 4H), 2.75 (m,1H), 2.15 (m,2H), 1.95 (m, 1H), 1.85 (m, 1H), 1.65 (m, 5H), 1.40 (m, 1H):

MS (+ve ESI): 675 (M+H)⁺

MS (−ve ESI): 673 (M−H)⁻.

di(tert-butyl)2-(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28a, but    starting with 2-piperidinylethanol (1.61 g, 9.0 mmol) and    N-(2-fluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.68 g, 3.0 mmol), and purifying the product by reverse phase HPLC    eluting with 40% acetonitrile in water containing 0.1% TFA, yielded    N-(2-fluorophenyl)-2-(2-((7-(3-(2-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (565 mg, 32% yield):

¹H-NMR (DMSO d₆): 9.95 (s, 1H), 8.48 (s, 1H), 7.90 (m, 2H), 7.25 (m,2H), 7.13 (m, 2H), 7.08 (s, 1H), 4.40 (br s, 1H), 4.10 (t, 2H), 3.90 (s,3H), 3.88 (s, 2H), 3.40 (m, 2H), 2.77 (m, 2H), 2.45 (m, 2H), 2.20 (m,1H), 1.90 (m, 2H), 1.75 (m, 1H), 1.57 (m, 2H), 1.47 (m, 3H),

1.27 (m, 2H):

MS (+ve ESI): 595 (M+H)⁺

MS (−ve ESI): 593 (M−H)⁻.

-   b) An analogous reaction to that described in example 28b, but    starting with    N-(2-fluorophenyl)-2-(2-((7-(3-(2-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (517 mg, 0.87 mmol) yielded di(tert-butyl)    2-(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    phosphate (484 mg, 71% yield) as a yellow gum:

MS (+ve ESI): 787 (M+H)⁺

MS (−ve ESI): 785 (M−H)⁻.

EXAMPLE 32 Preparation of Compound 32 in Table1—((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

Di(tert-butyl)((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (230 mg, 0.296 mmol) in 1,4-dioxane (15 ml) was treated with4.0 N hydrochloric acid in 1,4-dioxane (0.9 ml, 3.43 mmol) at 20° C. for18 hours. The solid product was collected by suction filtration, washedwith i) 1,4-dioxane (50 ml), ii) acetonitrile (50 ml) and iii) diethylether (50 ml) and then dried in vacuo to yield the title compound (166mg, 72% yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.45 (s, 1H), 9.00 (s, 1H), 7.85 (s, 1H), 7.67 (m,1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.20 (m, 2H), 4.28 (m, 2H), 4.20 (m,2H), 4.09 (s, 2H), 3.95 (s, 3H), 3.80 (m, 1H), 3.68 (m, 1H), 3.58 (m,1H), 3.25 (m, 2H), 2.30 (m, 2H), 2.20 (m, 1H), 2.00 (m, 2H), 1.85 (m,1H):

MS (+ve ESI): 665 (M+H)⁺

MS (−ve ESI): 663 (M−H)⁻.

di(tert-butyl)((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1p, but    starting with (2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetic    acid (26.7 g, 67 mmol) and 2,3-difluoroaniline (8.80 ml, 87 mmol)    yielded    N-(2,3-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (15.4 g, 95% yield):

¹H-NMR (DMSO d₆): 10.02 (s, 1H), 8.33 (s, 1H), 7.60 (m, 1H), 7.11-7.31(m, 16H), 6.58 (s, 1H), 3.63 (s, 2H):

MS (+ve ESI): 512 (M+H)⁺

-   b) An analogous reaction to that described in example 1g, but    starting with    N-(2,3-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (4.70 g, 9.2 mmol) yielded    N-(2,3-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (2.20 g, 46% yield):

¹H-NMR (DMSO d₆): 11.96 (br s, 1H), 10.20 (br s, 1H), 8.66 (s, 1H), 8.10(s, 1H), 7.70 (m, 1H), 7.36 (s, 1H), 7.28 (s, 1H), 7.18 (m, 2H), 4.26(t, 2H), 3.95 (s, 2H), 3.93 (s, 3H), 3.81 (t, 2H), 2.25 (m, 2H):

MS (+ve ESI): 520 (M+H)⁺

MS (−ve ESI): 518 (M−H)⁻.

-   c)    N-(2,3-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.04 g, 2.0 mmol) in dimethylacetamide (5 ml) was reacted with    D-prolinol (615 mg, 6.0 mmol) in the presence of tetrabutylammonium    iodide (100 mg, 0.27 mmol) at 60° C., under an inert atmosphere, for    17 hours. The cooled reaction solution was purified by reverse phase    HPLC eluting with 40% acetonitrile in water containing 0.1% TFA.    After basification of the product fractions with sodium carbonate    and concentration to low volume, the solid product was collected by    suction filtration, washed with water and dried in vacuo, to yield    N-(2,3-difluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (687 mg, 59% yield):

¹H-NMR (DMSO d₆): 10.20 (s, 1H), 8.55 (s, 1H), 8.00 (s, 1H), 7.70 (m,1H), 7.30 (s, 1H), 7.20 (m, 3H), 4.35 (br s, 1H), 4.20 (m, 2H), 3.90 (s,2H), 3.90 (s, 3H), 3.40 (m, 1H), 3.18 (m, 1H), 3.07 (m, 1H), 2.95 (m,1H), 2.40 (m, 2H), 2.15 (m, 1H), 1.93 (m, 2H), 1.80 (m, 1H), 1.67 (m,2H), 1.55 (m, 1H):

MS (+ve ESI): 585 (M+H)⁺.

-   d)    N-(2,3-difluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (620 mg, 1.06 mmol) in dimethylacetamide (6 ml) was treated with    tetrazole (148 mg, 2.12 mmol) and    di-tert-butyl-diethylphosphoramidite (800 mg, 2.6 mmol) at 20° C.,    under an inert atmosphere, for 6 hours. The reaction solution was    cooled to −10° C. and 30% hydrogen peroxide solution (0.3 ml, 2.6    mmol) was added dropwise over 5 minutes. After stirring for 2 hours    at 20° C. the reaction was quenched at −10° C. with 0.5 N sodium    thiosulphate solution (3 ml). The mixture was extracted twice with    ethyl acetate (25 ml) and the organic solution dried over magnesium    sulphate, evaporated and the resulting oil purified by    chromatography on silica gel, eluting with dichloromethane:7.0 N    methanolic ammonia (0-5%); evaporation of solvent and drying in    vacuo yielded di(tert-butyl)    ((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (393 mg, 48% yield) as a yellow gum:

¹H-NMR (DMSO d₆): 12.00 (br s, 1H), 10.27 (s, 1H), 8.66 (s, 1H), 8.10(s, 1H), 7.72 (m, 1H), 7.39 (s, 1H), 7.25 (s, 1H), 7.19 (m, 1H), 4.18(m, 2H), 3.99 (s, 2H), 3.95 (s, 3H), 3.79 (m, 1H), 3.55 (m, 1H), 3.10(m, 1H), 2.95 (m, 1H), 2.68 (m, 1H), 2.47 (m, 1H), 2.20 (m, 1H),1.80-2.00 (m, 3H), 1.50-1.75 (m, 3H), 1.35 (s, 18H):

MS (+ve ESI): 777 (M+H)⁺

MS (−ve ESI): 775 (M−H)⁻.

EXAMPLE 33 Preparation of Compound 33 in Table1—((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 32, but starting withdi(tert-butyl)((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (202 mg, 0.26 mmol) yielded the title compound (177 mg, 88%yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.45 (s, 1H), 9.00 (s, 1H), 7.85 (s, 1H), 7.65 (m,1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.20 (m, 2H), 4.30 (m, 2H), 4.20 (m,2H), 4.08 (s, 2H), 3.98 (s, 3H), 3.55-3.80 (m, 3H), 3.15-3.35 (m, 2H),2.15-2.45 (m, 3H), 1.78-2.08 (m, 3H):

MS (+ve ESI): 665 (M+H)⁺

MS (−ve ESI): 663 (M−H)⁻.

di(tert-butyl)((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c, but    starting with L-prolinol (583 mg, 5.7 mmol) and    N-(2,3-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (982 mg, 1.89 mmol). Purification was by reverse phase HPLC, eluting    with 40% acetonitrile in water containing 0.1% TFA. After    basification of the product fractions with sodium carbonate and    concentration to low volume, the solid product was collected by    suction filtration, washed with water and dried in vacuo, to yield    N-(2,3-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (562 mg, 51% yield):

¹H-NMR (DMSO d₆): 10.25 (s, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 7.70 (m,1H), 7.35 (s, 1H), 7.17 (m, 3H), 4.32 (br s, 1H), 4.15 (m, 2H), 3.95 (s,2H), 3.90 (s, 3H), 3.38 (m, 1H), 3.15 (m, 1H), 3.05 (m, 1H), 2.95 (m,1H), 2.40 (m, 2H), 2.12 (m, 1H), 1.95 (m, 2H), 1.78 (m, 1H), 1.60 (m,2H), 1.55 (m, 1H):

MS (+ve ESI): 585 (M+−H)⁺

MS (−ve ESI): 583 (M−H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (501 mg, 0.858 mmol) yielded di(tert-butyl)    ((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (205 mg, 31% yield) as a yellow gum:

MS (+ve ESI): 777 (M+H)⁺

MS (−ve ESI): 775 (M−H)⁻.

EXAMPLE 34 Preparation of Compound 34 in Table1—2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 32, but starting withdi(tert-butyl)2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethylphosphate (503 mg, 0.67 mmol) yielded the title compound (478 mg, 96%yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.45 (s, 1H), 9.00 (s, 1H), 7.85 (s, 1H), 7.65 (m,1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.18 (m, 2H), 4.25 (m, 4H), 4.05 (s,2H), 3.95 (s, 3H), 3.42 (m, 2H), 3.30 (m, 2H), 2.85 (s, 3H), 2.30 (m,2H):

MS (+ve ESI): 639 (M+H)⁺

MS (−ve ESI): 637 (M−H)⁻.

di(tert-butyl)2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c, but    starting with 2-(methylamino)ethanol (496 mg, 6.6 mmol) and    N-(2,3-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.14 g, 2.2 mmol) yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-6-methoxyquinazolin-4yl)amino)-1,3-thiazol-5-yl)acetamide    (681 mg, 55% yield):

¹H-NMR (DMSO d₆): 10.15 (s, 1H), 8.53 (s, 1H), 7.98 (s, 1H), 7.70 (m,1H), 7.28 (s, 1H), 7.15 (m, 2H), 4.15 (m, 2H), 3.92 (s, 2H), 3.90 (s,3H), 3.48 (m, 2H), 2.50 (m, 2H), 7.42 (m, 2H), 2.20 (s, 3H), 1.90 (m,2H):

MS (+ve ESI): 559 (M+H)⁺

MS (−ve ESI): 557 (M−H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)(methyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (617 mg, 1.106 mmol) yielded di(tert-butyl)    2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyl    phosphate (503 mg, 61% yield) as a yellow gum:

MS (+ve ESI): 751 (M+H)⁺

MS (−ve ESI): 749 (M−H)⁻.

EXAMPLE 35 Preparation of Compound 35 in Table1—2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 32 but starting withdi(tert-butyl)2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethylphosphate (133 mg, 0.166 mmol) yielded the title compound (136 mg, 98%yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.75 (s, 1H), 10.40 (s, 1H), 9.00 (s, 1H), 7.87 (s,1H), 7.65 (m, 1H), 7.60 (s, 1H), 7.42 (s, 1H), 7.19 (m, 2H), 4.28 (m,2H), 4.05 (s, 2H), 3.95 (s, 3H), 3.95 (m, 2H), 3.02-3.50 (m, 5H), 2.30(m, 2H), 1.40-2.10 (m, 6H):

MS (+ve ESI): 693 (M+H)⁺

MS (−ve ESI): 691 (M−H)⁻.

di(tert-butyl)2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c, but    starting with 2-(2-hydroxyethyl)piperidine (588 mg, 6.6 mmol) and    N-(2,3-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.14 g, 2.2 mmol), yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-(2-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (260 mg, 19% yield):

¹H-NMR (DMSO d₆): 10.10 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H), 7.70 (m,1H), 7.25 (s, 1H), 7.18 (m, 2H), 7.09 (s, 1H), 4.35 (br s, 1H), 4.10 (m,2H), 3.90 (s, 3H), 3.89 (s, 2H), 3.45 (m, 1H), 2.75 (m, 2H), 2.45 (m,2H), 2.25 (m, 1H), 1.90 (m, 2H), 1.75 (m, 1H), 1.57 (m, 2H), 1.45 (m,3H), 1.28 (m, 2H):

MS (+ve ESI): 613 (M+H)⁺

MS (−ve ESI): 611 (M−H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-(2-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (219 mg, 0.358 mmol) yielded di(tert-butyl)    2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    phosphate (133 mg, 46% yield) as a yellow gum:

MS (+ve ESI): 805 (M+H)⁺

MS (−ve ESI): 803 (M−H)⁻.

EXAMPLE 36 Preparation of Compound 36 in Table1—2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 32 but starting withdi(tert-butyl)2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethylphosphate (354 mg, 0.46 mmol) and the resulting yellow solid waspurified by chromatography on silica gel, eluting withdichloromethane:methanol:water:formic acid (100:40:8:8); evaporation ofsolvent and drying in vacuo yielded the title compound (194 mg, 55%yield) as a yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.30 (s, 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.70 (m,1H), 7.35 (s, 1H), 7.25 (s, 1H), 7.18 (m, 2H), 4.20 (m, 2H), 3.95 (s,2H), 3.93 (s, 3H), 3.90 (m, 2H), 2.95 (m, 4H), 2.87 (m, 2H), 2.10 (m,2H), 1.10 (t, 3H):

MS (+ve ESI): 653 (M+H)⁺

MS (−ve ESI): 651 (M−H)⁻.

di(tert-butyl)2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c, but    starting with 2-(ethylamino)ethanol (588 mg, 6.6 mmol) and    N-(2,3-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.14 g, 2.2 mmol), yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (345 mg, 28% yield):

¹H-NMR (DMSO d₆): 10.20 (s, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 7.70 (m,1H), 7.35 (m, 1H), 7.15 (m, 3H), 4.28 (br s, 1H), 4.16 (m, 2H), 3.94 (s,2H), 3.93 (s, 3H), 3.42 (m, 2H), 2.60 (m, 2H), 2.50 (m, 6H), 1.90 (m,2H), 0.95 (t, 3H):

MS (+ve ESI): 572 (M+H)⁺

MS (−ve ESI): 571 (M−H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (293 mg, 0.512 mmol) yielded di(tert-butyl)    2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    phosphate (354 mg, 91% yield) as a yellow gum:

MS (+ve ESI): 765(M+H)⁺

MS (−ve ESI): 763 (M−H)⁻.

EXAMPLE 37 Preparation of Compound 37 in Table1—1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyldihydrogen phosphate

An analogous reaction to that described in example 32, but starting withdi(tert-butyl)1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethylphosphate (983 mg, 1.24 mmol) yielded the title compound (993 mg, 100%yield):

¹H-NMR (DMSO d₆): 10.45 (br s, 2H), 9.00 (s, 1H), 7.90 (s, 1H),7.60-7.70 (m, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 7.10-7.25 (m, 1H),4.30-4.40 (m, 2H), 4.10 (s, 2H), 3.98 (m, 3H), 3.68 (m, 2H), 3.50-3.60(m, 2H), 3.22 (m, 2H), 2.90-3.00 (m, 2H), 2.30-2.45 (m, 2H), 1.80-1.90(m, 2H), 1.55-1.65 (m, 2H):

MS (+ve ESI): 679.4 (M+H)⁺.

di(tert-butyl)1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c, but    starting with    N-(2,3-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (2.00 g, 3.85 mmol) and 4-(hydroxymethyl)piperidine (2.22 g, 19.3    mmol) yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (1.30 g, 56% yield):

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.25 (s, 1H), 8.70 (s, 1H), 8.15 (s,1H), 7.65-7.75 (m, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 7.00-7.10 (m, 2H),4.40 (br s, 1H), 4.10-4.20 (m, 2H), 3.98 (s, 3H), 3.96 (s, 2H), 3.33 (m,6H), 1.80-2.00 (m, 2H), 1.60-1.70 (m, 2H), 1.40-1.50 (m, 1H), 1.10-1.20(m, 2H):

MS (+ve ESI): 599.6 (M+H)⁺

MS (−ve ESI): 597.6 (M−H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (1.34 g, 2.25 mmol) yielded di(tert-butyl)    1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyl    phosphate (983 mg, 55% yield):

¹H-NMR (DMSO d₆): 11.80 (s, 1H), 10.20 (s, 1H), 8.65 (s, 1H), 8.10 (s,1H), 7.67 (m, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 7.18 (m, 2H), 4.20 (t,2H), 3.98 (s, 3H), 3.96 (s, 2H), 3.75 (m, 1H), 2.80-2.90 (m, 1H),2.40-2.50 (m, 4H), 1.90-2.00 (m, 4H), 1.60-1.70 (m, 2H), 1.56 (m, 1H),1.40 (s, 18H), 1.10-1.20 (m, 2H):

MS (+ve ESI): 791 (M+H)⁺.

EXAMPLE 38 Preparation of Compound 38 in Table1—2-(4-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 32, but starting withdi(tert-butyl)2-(4-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethylphosphate (866 mg, 1.08 mmol) yielded the title compound (898 mg,quantitative yield):

¹H-NMR (DMSO d₆): 10.50 (s, 1H), 9.00 (s, 1H), 7.90 (s, 1H), 7.78 (m,1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.10-7.25 (m, 2H), 4.30-4.40 (m, 4H),4.10 (s, 2H), 4.00 (s, 3H), 3.50-3.90 (m, 8H), 3.42 (m, 2H), 3.30 (m,2H), 2.30-2.40 (m, 2H):

³¹P-NMR (¹H) (DMSO d₆): 0.46 (s, 1P):

MS (+ve ESI): 694 (M+H)⁺.

di(tert-butyl)2-(4-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c, but    starting with N-(2-hydroxyethyl)piperazine (2.50 g, 19.2 mmol)    yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-(1-(4-(2-hydroxyethyl))piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (1.08 g, 46% yield):

¹H-NMR (DMSO d₆): 12.02 (s, 1H), 10.30 (s, 1H), 8.70 (s, 1H), 8.01 (s,1H), 7.60-7.70 (m, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.13 (m, 2H), 4.40(br s, 1H), 4.20 (t, 2H), 3.98 (s, 2H), 3.95 (s, 3H), 3.57 (m, 2H),2.40-2.50 (m, 10H), 1.90-2.00 (m, 2H):

MS (+ve ESI): 614 (M+H)⁺

MS (−ve ESI): 612 (M+H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-(1-(4-(2-hydroxyethyl))piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (1.08 g, 1.76 mmol) yielded di(tert-butyl)    2-(4-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyl    phosphate (866 mg, 61% yield):

¹H-NMR (DMSO d₆): 12.01 (s, 1H), 10.30 (s, 1H), 8.70 (s, 1H), 8.20 (s,1H), 7.60-7.70 (m, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.14 (m, 2H), 4.20(t, 2H), 3.98 (s, 2H), 3.90 (s, 3H), 3.82 (m, 2H), 2.66 (m, 2H),2.30-2.40 (m, 8H), 1.90-2.00 (m, 2H), 1.40 (s, 18H):

MS (+ve ESI): 806 (M+H)⁺.

EXAMPLE 39 Preparation of Compound 39 in Table1—3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbutyldihydrogen phosphate

An analogous reaction to that described in example 32, but starting withdi(tert-butyl)3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbutylphosphate (168 mg, 0.22 mmol) yielded the title compound (160 mg,quantitative yield):

¹H-NMR (DMSO d₆): 10.50 (s, 1H), 9.15 (br s, 2H), 9.02 (s, 1H), 7.90 (s,1H), 7.60-7.70 (m, 1H), 7.60 (s, 1H), 7.40 (s, 1H), 7.10-7.20 (m, 2H),4.40 (t, 2H), 4.10 (s, 2H), 4.01 (s, 3H), 3.92 (m, 2H), 3.00-3.10 (m,2H), 2.30-2.50 (m, 2H), 2.00-2.10 (m, 2H), 1.45 (s, 6H):

MS (+ve ESI): 667 (M+H)⁺.

di(tert-butyl)3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbutylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c but    starting with 3-amino-3-methyl-1-butanol (1.98 g, 19.3 mmol) yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-((1-hydroxy-3-methylbut-3-yl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (168 mg, 7% yield):

¹H-NMR (DMSO d₆): 10.40 (s, 1H), 8.70 (s, 1H), 8.10 (s, 1H), 7.60-7.70(m, 1H), 7.35 (s, 1H), 7.10-7.20 (m, 2H), 4.20 (t, 2H), 3.98 (s, 3H),3.95 (s, 2H), 3.50 (t, 2H), 2.60-2.70 (m, 2H), 1.90-2.00 (m, 2H), 1.50(t, 2H), 1.01 (s, 6H):

MS (+ve ESI): 587(M+H)⁺

MS (−ve ESI): 585 (M+H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-((1-hydroxy-3-methylbut-3-yl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (168 mg, 0.29 mmol) yielded di(tert-butyl)    3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbut-3-yl    phosphate (168 mg, 75% yield):

MS (+ve ESI): 779 (M+H)⁺.

EXAMPLE 40 Preparation of Compound 40 in Table1—2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyldihydrogen phosphate

An analogous reaction to that described in example 32, but starting withdi(tert-butyl)2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropylphosphate (230 mg, 0.30 mmol) yielded the title compound (150 mg, 70%yield):

¹H-NMR (DMSO d₆): 10.50 (s, 1H), 9.15 (br s, 2H), 9.00 (s, 1H), 7.90 (s,1H), 7.60-7.70 (m, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 7.10-7.20 (m, 2H),4.35 (t, 2H), 4.10 (s, 2H), 4.00 (s, 3H), 3.92 (m, 2H), 3.00-3.10 (m,2H), 2.30-2.40 (m, 2H), 1.45 (s, 6H):

MS (+ve ESI): 653 (M+H)⁺.

di(tert-butyl)2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c, but    starting with 2-amino-2-methyl-1-propanol (1.71 g, 19.3 mmol)    yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-((3-hydroxy-2-methylprop-2-yl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (478 mg, 23% yield):

¹H-NMR (DMSO d₆): 10.20 (s, 1H), 8.70 (s, 1H), 8.20 (s, 1H), 7.70-7.80(m, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.17 (m, 2H), 4.40 (br s, 1H), 4.20(t, 2H), 3.98 (s, 2H), 3.95 (s, 3H), 3.20 (s, 2H), 2.70 (t, 2H),1.90-2.00 (m, 2H), 1.01 (s, 6H):

MS (+ve ESI): 573 (M+H)⁺

MS (−ve ESI): 571 (M+H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-((3-hydroxy-2-methylprop-2-yl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (430 mg, 0.75 mmol) yielded di(tert-butyl)    2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyl    phosphate (230 mg, 40% yield):

MS (+ve ESI): 765 (M+H)⁺.

EXAMPLE 41 Preparation of Compound 41 in Table1—2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 32, but starting withdi(tert-butyl)2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethylphosphate (716 mg, 0.877 mmol) yielded the title compound (200 mg, 36%yield):

¹H-NMR (DMSO d₆): 10.00 (br s, 1H), 8.60 (s, 1H), 8.09 (s, 1H), 7.65 (m,1H), 7.30 (s, 1H), 7.27 (s, 1H), 7.13 (m, 2H), 4.25 (m, 2H), 3.95 (m,7H), 3.00 (m, 4H), 2.10 (m, 2H):

MS (+ve ESI): 625 (M−H)⁺

MS (−ve ESI): 623 (M−H)⁻.

di(tert-butyl)2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 32c, but    starting with ethanolamine (403 mg, 6.60 mmol) yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (503 mg, 81% yield):

¹H-NMR (DMSO d₆): 10.31 (s, 1H), 8.89 (s, 1H), 8.55 (br s, 2H), 8.01 (brs, 1H), 7.70 (m, 1H), 7.50 (s, 1H), 7.31 (s, 1H), 7.18 (m, 2H), 4.26 (m,2H), 4.02 (s, 2H), 3.96 (s, 3H), 3.67 (m, 2H), 3.15 (m, 2H), 3.08 (m,2H), 2.20 (m, 2H):

MS (+ve ESI): 545 (M−H)⁺

MS (−ve ESI): 543 (M−H)⁻.

-   b) An analogous reaction to that described in example 32d, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(3-((2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (450 mg, 0.83 mmol) yielded di(tert-butyl)    2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyl    phosphate (716 mg) as an off-white solid which was used without    further purification.

EXAMPLE 42 Preparation of Compound 42 in Table1—((2R)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)((2R)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (448 mg, 0.577 mmol) yielded the title compound as thedihydrochloride salt (424 mg, 99% yield):

¹H-NMR (DMSO d₆): 10.45 (s, 1H), 9.10 (s, 1H), 8.00 (m, 2H), 7.70 (s,1H), 7.35-7.45 (m, 1H), 7.05 (m, 1H), 4.15-4.40 (m, 1H), 4.10 (s, 2H),4.00 (s, 3H), 3.80 (t, 1H), 3.50-3.70 (m, 2H), 3.20-3.40 (m, 2H),2.35-2.50 (m, 2H), 2.25 (m, 2H), 1.97 (m, 2H), 1.85 (m, 1H);

MS (+ve ESI): 665(M+H)⁺.

di(tert-butyl)((2R)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1p, but    starting with (2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetic    acid (10.0 g, 25 mmol) and 2,5-difluoroaniline (0.73 ml, 7.56 mol)    yielded    N-(2,5-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (1.25 g, 61% yield):

MS (+ve ESI): 352 (M+H)⁺.

-   b) Trifluoroacetic acid (20 ml) was added to a solution of    N-(2,5-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (12.8 g, 25 mmol) in dichloromethane (200 ml) and the reaction    allowed to stir for 16 hours at ambient temperature before solvent    evaporation in vacuo. The crude product was washed with saturated    aqueous sodium hydrogen carbonate solution and then purified by    chromatography on silica gel, eluting with 5-20% methanol in    dichloromethane to yield    2-(2-amino-1,3-thiazol-5-yl)-N-(2,5-difluorophenyl)acetamide (2.64    g, 39% yield) as a beige solid:

¹H-NMR (DMSO d₆): 7.82 (m, 1H), 7.28 (m, 1H), 6.93 (m, 1H), 6.70 (m,3H), 3.74 (s, 2H), 2.25 (m, 2H):

MS (+ve ESI): 270 (M+H)⁺

MS (−ve ESI): 268 (M−H)⁻.

-   c) A mixture of    2-(2-amino-1,3-thiazol-5-yl)-N-(2,5-difluorophenyl)acetamide (2.64    g, 9.8 mmol) and    1-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (2.90 g, 9.8 mmol) was heated in acetic acid (15 ml) at 145° C. for    5 hours. The reaction mixture was cooled to ambient temperature,    methanol (2 ml) and diethyl ether (30 ml) were added and the yellow    solid was collected by suction filtration. The crude product was    washed with i) acetic acid, ii) acetontrile and iii) diethyl ether    and then taken up in dimethylacetamide (15 ml). Saturated aqueous    sodium hydrogen carbonate solution (200 ml) was added and the    reaction stirred for 30 minutes at ambient temperature before a    solid was collected by suction filtration. Drying in vacuo yielded    N-(2,5-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (3.23 g, 63% yield) as a pale yellow solid:

¹H-NMR DMSO d₆): 10.15 (br s, 1H), 8.58 (s, 1H), 8.01 (s, 1H), 7.89 (m,1H), 7.36 (m, 2H), 7.19 (s, 1H), 6.95 (m, 1H), 4.25 (t, 2H), 3.95 (m,5H), 3.80 (t, 2H), 2.25 (m, 2H);

MS (+ve ESI): 520 (M+H)⁺

MS (−ve ESI): 518 (M−H)⁻.

-   d) An analogous reaction to that described in example 1h, but    starting with    N-(2,5-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.00 g, 1.93 mmol) and D-prolinol (0.95 ml, 9.60 mmol) yielded    N-(2,5-difluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (745 mg, 63% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO d₆): 10.32 (s, 1H), 9.23 (br s, 1H), 8.94 (s, 1H), 8.00 (s,1H), 7.91 (m, 1H), 7.58 (s, 1H), 7.31-7.40 (m, 2H), 7.04 (m, 1H), 4.29(m, 2H), 4.04 (s, 2H), 3.96 (s, 3H), 3.60 (m, 3H), 3.22 (m, 2H), 2.29(m, 2H), 2.00-2.18 (m, 2H), 1.92 (m, 1H), 1.79 (m, 1H):

MS (+ve ESI): 585 (M+H)⁺

MS (−ve ESI): 583 (M−H)⁻.

-   e) An analogous reaction to that described in example 1i, but    starting with    N-(2,5-difluorophenyl)-2-(2-((7-(3-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (704 mg, 1.20 mmol) yielded di(tert-butyl)    ((2R)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (448 mg, 48% yield):

¹H-NMR (DMSO d₆): 8.62 (s, 1H), 8.10 (m, 1H), 7.89 (m, 1H), 7.20-7.38(m, 3H), 6.96 (m, 1H), 4.20 (m, 2H), 4.10 (s, 2H), 3.97 (s, 2H), 3.93(s, 3H), 3.74 (m, 1H), 3.55 (m, 1H), 3.06 (m, 1H), 2.93 (m, 1H), 2.65(m, 1H), 2.20 (m, 1H), 1.80-1.96 (m, 3H), 1.52-1.70 (m, 3H), 1.36 (s,18H):

MS (+ve ESI): 777.5 (M+H)⁺.

EXAMPLE 43 Preparation of Compound 43 in Table1—((2S)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)((2S)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (500 mg, 0.644 mmol) yielded the title compound as thedihydrochloride salt (459 mg, 99% yield):

¹H-NMR (DMSO d₆): 10.45 (s, 1H), 9.10 (s, 1H), 8.0 (m, 2H), 7.70 (s,1H), 7.35-7.45 (m, 1H), 7.05 (m, 1H), 4.15-4.40 (m, 1H), 4.10 (s, 2H),4.00 (s, 3H), 3.80 (t, 1H), 3.50-3.70 (m, 2H), 3.20-3.40 (m, 2H),2.35-2.50 (m, 2H), 2.25 (m, 2H), 1.97 (m, 2H), 1.85 (m, 1H);

MS (+ve ESI): 665(M+H)⁺.

di(tert-butyl)((2S)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 42d, but    starting with L-prolinol (0.95 ml, 9.60 mmol) yielded    N-(2,5-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (612 mg, 52% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO d₆): 10.07 (s, 1H), 8.95 (br s, 1H), 8.70 (s, 1H), 7.81 (s,1H), 7.70 (m, 1H), 7.34 (s, 1H), 7.05-7.25 (m, 2H), 6.81 (m, 1H), 4.08(m, 2H), 3.80 (s, 2H), 3.72 (s, 3H), 3.50 (m, 3H), 2.99 (m, 2H), 2.04(m, 2H), 1.80-1.98 (m, 2H), 1.65 (m, 1H), 1.55 (m, 1H):

MS (+ve ESI): 585 (M+H)⁺

MS (−ve ESI): 583 (M−H)⁻.

-   b) An analogous reaction to that described in example 42e, but    starting with    N-(2,5-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (571 mg, 0.98 mmol) yielded di(tert-butyl)    ((2S)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (500 mg, 66% yield):

¹H-NMR (DMSO d₆): 8.62 (s, 1H), 8.09 (m, 1H), 7.90 (m, 1H), 7.37 (s,1H), 7.32 (m, 1H), 7.21 (s, 1H), 6.96 (m, 1H), 4.20 (m, 2H), 4.10 (s,2H), 3.98 (s, 2H), 3.93 (s, 3H), 3,74 (m, 1H), 3.55 (m, 1H), 3.06 (m,1H), 2.93 (m, 1H), 2.65 (m, 1H), 2.20 (m, 1H), 1.80-1.96 (m, 3H),1.52-1.70 (m, 3H), 1.36 (s, 18H):

MS (+ve ESI): 777.5 (M+H)⁺.

EXAMPLE 44 Preparation of Compound 44 in Table1—2-((3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-((3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethylphosphate (233 mg, 0.305 mmol) yielded the title compound as thedihydrochloride salt (222 mg, 99% yield):

¹H-NMR (DMSO d₆): 10.50 (s, 1H), 9.05 (s, 1H), 7.96 (m, 2H), 7.70 (s,1H), 7.60 (s, 1H), 7.40-7.50 (m, 1H), 6.90-7.10 (m, 1H), 4.30-4.40 (m,4H), 4.10 (s, 2H), 4.02 (s, 3H), 3.40-3.50 (m, 2H), 3.20-3.30 (m, 4H),2.30-2.40 (m, 2H), 1.30 (t, 3H):

MS (+ve ESI): 653 (M+H)⁺.

di(tert-butyl)2-((3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 42d, but    starting with N-ethylethanolamine (0.66 ml, 6.75 mmol) yielded    N-(2,5-difluorophenyl)-2-(2-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (312 mg, 40% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO d₆): 10.15 (s, 1H), 8.60 (s, 1H), 8.00 (s, 1H), 7.80-7.90(m, 1H), 7.25-7.40 (m, 1H), 7.20 (s, 1H), 6.90-7.00 (m, 1H), 4.25 (br s,1H), 4.20 (t, 2H), 3.98 (s, 2H), 3.95 (s, 3H), 3.42 (m, 2H), 2.57 (m,2H), 2.40-2.50 (m, 4H), 1.80-1.95 (m, 2H), 1.30 (t, 3H):

MS (+ve ESI): 573 (M+H)⁺

MS (−ve ESI): 571 (M−H)⁻.

-   b) An analogous reaction to that described in example 42e, but    starting with    N-(2,5-difluorophenyl)-2-(2-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (294 mg, 0.51 mmol) yielded di(tert-butyl)    2-((3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl    phosphate (233 mg, 60% yield):

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.30 (s, 1H), 8.70 (s, 1H), 8.20 (s,1H), 7.80-7.90 (m, 1H), 7.40 (s, 1H), 7.33 (m, 1H), 7.20 (s, 1H), 6.95(m, 1H), 4.20 (t, 2H), 3.90 (s, 2H), 3.80 (s, 3H), 3.75 (m, 2H), 2.68(m, 4H), 2.50-2.60 (m, 2H), 1.88 (m, 2H), 1.40 (s, 18H), 1.30 (t, 3H):

MS (+ve ESI): 765 (M+H)⁺.

EXAMPLE 45 Preparation of Compound 45 in Table1—((2S)-1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)((2S)-1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate (261 mg, 0.336 mmol) yielded the title compound (218 mg, 88%yield):

¹H-NMR (DMSO d₆): 10.15 (br s, 1H), 9.00 (s, 1H), 7.90 (s, 1H),7.70-7.80 (m, 1H), 7.60 (s, 1H), 7.40 (s, 1H), 7.20-7.30 (m, 1H), 7.12(m, 1H), 4.30-4.40 (m, 2H), 4.15-4.25 (m, 2H), 4.10 (s, 2H), 3.95 (s,3H), 3.50-3.90 (m, 3H), 3.10-3.40 (m, 2H), 1.80-2.40 (m, 8H):

MS (+ve ESI): 665 (M+H)⁺.

di(tert-butyl)((2S)-1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methylphosphate used as the starting material was obtained as follows:

-   a) A solution of sodium hydroxide (30 g, 760 mmol) in water (60 ml)    was added to a solution of methyl (2-amino-1,3-thiazol-5-yl)acetate    hydrobromide (see example 1l)) (64 g, 250 mmol) in methanol (600 ml)    and the reaction was stirred at ambient temperature for 3 hours. The    methanol was removed in vacuo and the residue acidified to pH 3.5 by    addition of 1.0 N hydrochloric acid. The orange solid was collected    by suction filtration, washed with water and dried in vacuo to yield    (2-amino-1,3-thiazol-5-yl)acetic acid (48.4 g, quantitative yield)    as a pale orange solid:

¹H-NMR (DMSO d₆): 6.72 (br s, 2H), 6.69 (s, 1H), 3.54 (s, 2H):

MS (+ve ESI): 159 (M+H)⁺.

-   b) A solution of    N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (22.6 g, 76.7 mmol) and (2-amino-1,3-thiazol-5-yl)acetic acid (12.1    g, 76.7 mmol) in acetic acid (230 ml) was heated at reflux for 5    hours. The reaction was cooled to ambient temperature, the solid was    collected by suction filtration and then taken up in water (250 ml)    and heated at 100° C. for 20 minutes. The reaction was cooled, the    solid was filtered off and washed with water. Drying in vacuo    yielded    2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetic    acid (24.7 g, 79% yield) as a cream solid:

¹H-NMR (DMSO d₆): 8.65 (s, 1H), 8.08 (s, 1H), 7.33 (s, 1H), 7.27 (s,1H), 4.37 (t, 2H), 3.95 (s, 3H), 3.80 (m, 4H), 2.25 (m, 2H):

MS (+ve ESI): 409 (M+H)⁺.

-   c) 2,4-Difluoroaniline (2.99 ml, 29.4 mmol) and    4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride    (7.46 g, 27.0 mmol) were added to a stirred solution of    2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetic    acid (10.0 g, 24.5 mmol) in dimethylacetamide (150 ml) and the    reaction stirred for 45 hours at ambient temperature under an inert    atmosphere. The reaction was filtered and the filtrate diluted with    saturated aqueous sodium hydrogen carbonate solution (300 ml). The    product was collected by suction filtration and washed with i)    water, ii) acetonitrile and iii) ethyl acetate/hexane to give a    beige solid. This was stirred in water (500 ml) at 80° C. for 10    minutes, cooled to ambient temperature and the solid filtered off.    Drying in vacuo yielded    N-(2,4-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (6.34 g, 50% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 9.80 (s, 1H), 8.20 (s, 1H), 7.70-7.80 (m, 1H), 7.60(s, 1H), 7.20-7.30 (m, 1H), 7.00-7.10 (m, 2H), 6.90 (s, 1H), 4.00 (t,2H), 3.80 (s, 3H), 3.70 (t, 2H), 3.60 (s, 2H), 2.10-2.20 (m, 2H):

MS (+ve ESI): 520/522 (M+H)⁺

MS (−ve ESI): 518/520 (M−H)⁻.

-   d) An analogous reaction to that described in example 1h, but    starting with (S)-(+)-2-pyrrolidinylmethanol (1.46 g, 14.5 mmol) and    N-(2,4-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.49 g, 2.87 mmol) yielded    N-(2,4-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (670 mg, 40% yield):

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.00 (s, 1H), 8.70 (s, 1H), 8.10 (s,1H), 7.80-7.90 (m, 1H), 7.40 (s, 1H), 7.32 (m, 1H), 7.25 (s, 1H),7.00-7.10 (m, 1H), 4.40 (br s, 1H), 4.17 (m, 2H), 4.00 (s, 3H), 3.98 (s,2H), 3.30-3.40 (m, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.90-3.00 (m, 1H),2.40-2.50 (m, 2H), 2.19 (m, 1H), 1.90-2.00 (m, 2H), 1.70-1.80 (m, 1H),1.50-1.60 (m, 2H), 1.35-1.45 (m, 1H):

MS (+ve ESI): 585 (M+H)⁺

MS (−ve ESI): 583 (M−H)⁻.

-   e) An analogous reaction to that described in example 1i, but    starting with    N-(2,4-difluorophenyl)-2-(2-((7-(3-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)propoxy-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (614 mg, 1.05 mmol) yielded di(tert-butyl)    ((2S)-1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl    phosphate (280 mg, 34% yield):

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.00 (s, 1H), 8.65 (s, 1H), 8.20 (s,1H), 7.80-7.90 (m, 1H), 7.40 (s, 1H), 7.35 (m, 1H), 7.25 (s, 1H),7.00-7.10 (m, 1H), 4.15 (m, 2H), 4.00 (s, 3H), 3.98 (s, 2H), 3.70-3.80(m, 1H), 3.50-3.60 (m, 2H), 3.17 (m, 1H), 3.08 (m, 1H), 2.90-3.00 (m,1H), 2.60-2.70 (m, 1H), 2.17 (m, 1H), 1.80-2.00 (m, 2H), 1.50-1.60 (m,3H), 1.30 (s, 18H):

MS (+ve ESI): 777.7 (M+H)⁺.

EXAMPLE 46 Preparation of Compound 46 in Table1—2-(1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-(1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethylphosphate (181 mg, 0.225 mmol) yielded the title compound (134 mg, 78%yield):

¹H-NMR (DMSO d₆): 10.45 (s, 1H), 10.20 (s, 1H), 9.00 (s, 1H), 7.90 (s,1H), 7.82 (m, 1H), 7.60 (s, 1H), 7.40 (s, 1H), 7.45 (m, 1H), 7.00-7.10(m, 1H), 4.32 (m, 2H), 4.00 (s, 2H), 3.95 (s, 3H), 3.80-3.90 (m, 2H),3.55-3.65 (m, 1H), 3.10-3.50 (m, 6H), 2.30-2.40 (m, 2H), 1.50-2.10 (m,6H):

MS (+ve ESI): 693 (M+H)⁺.

di(tert-butyl)2-(1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 45d, but    starting with 2-piperidinylethanol (1.86 g, 14.4 mmol) and    N-(2,4-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.50 g, 2.89 mmol yielded    N-(2,4-difluorophenyl)-2-(2-((7-(3-(2-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (314 mg, 18% yield):

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.10 (s, 1H), 8.70 (s, 1H), 8.10 (s,1H), 7.88 (m, 1H), 7.40 (s,1H), 7.33 (m, 1H), 7.25 (s, 1H), 7.00-7.10(m, 1H), 4.20 (t, 2H), 3.98 (s, 3H), 3.96 (s, 2H), 3.40-3.50 (m, 2H),2.70-2.80 (m, 2H), 2.40-2.50 (m, 2H), 2.25 (m, 1H), 1.90-2.00 (m, 2H),1.70-1.80 (m, 1H), 1.30-1.60 (m, 5H), 1.20-1.30 (m, 2H):

MS (+ve ESI): 613 (M+H)⁺

MS (−ve ESI): 611 (M−H)⁻.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(2,4-difluorophenyl)-2-(2-((7-(3-(2-(2-hydroxyethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (279 mg, 0.46 mmol) yielded di(tert-butyl)    2-(1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyl    phosphate (181 mg, 49% yield):

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.00 (s, 1H), 8.65 (s, 1H), 8.20 (s,1H), 7.80-7.90 (m, 1H), 7.40 (s, 1H), 7.33 (m, 1H), 7.25 (s, 1H),7.00-7.10 (m, 1H), 4.18 (m, 2H), 4.00 (s, 3H), 3.98 (s, 2H), 3.80-3.90(m, 2H), 2.80-2.90 (m, 2H), 2.52 (m, 2H), 2.23 (m, 1H), 1.90-2.00 (m,3H), 1.50-1.70 (m, 5H), 1.40 (s, 18H), 1.32 (m, 2H):

MS (+ve ESI): 805 (M+H)⁺.

EXAMPLE 47 Preparation of Compound 47 in Table1—2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyldihydrogen phosphate

An analogous reaction to that described in example 1 but starting withdi-tert-butyl2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethylphosphate (634 mg, 0.83 mmol) yielded the title compound (595 mg, 97%yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.90 (s, 1H), 7.64 (s, 1H), 7.63(m, 1H), 7.36 (m, 2H), 7.35 (s, 1H), 6.91 (m, 1H), 4.31 (m, 4H), 4.01(s, 2H), 3.99 (s, 3H), 3.61 (m, 2H), 3.49 (m, 2H), 2.99 (m, 1H), 2.38(m, 2H), 1.10 (m, 2H), 0.94 (m, 2H):

MS (+ve ESI): 647 (M+H)⁺.

di-tert-butyl2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with cyclopropylamine (758 mg, 7.50 mmol) yielded    2-{2-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1,3-thiazol-5-yl}-N-(3-fluorophenyl)acetamide    (1.10 g, 77% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO d₆): 8.67 (s, 1H), 8.12 (s, 1H), 7.61 (d, 1H), 7.35 (m,3H), 7.24 (s, 1H), 6.90 (m, 1H), 4.30 (t, 1H), 3.16 (t, 2H), 3.96 (s,3H), 3.89 (s, 2H), 4.50 (m, 2H), 2.76 (t, 2H), 2.65 (t, 2H), 1.95 (m,2H), 1.82 (m, 1H), 0.42 (m, 2H), 0.30 (m, 2H):

MS (+ve ESI): 567 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    2-{2-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1,3-thiazol-5-yl}-N-(3-fluorophenyl)acetamide    (793 mg, 1.40 mmol) yielded di-tert-butyl    2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl    phosphate (630 mg, 59% yield):

¹H-NMR (DMSO d₆, TFA): 9.09 (s, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.63(m, 1H), 7.36 (m, 2H), 7.32 (s, 1H), 6.91 (m, 1H), 4.31 (m, 4H), 4.00(s, 2H), 3.99 (s, 3H), 3.64 (m, 2H), 3.51 (m, 2H), 2.99 (m, 1H), 2.36(m, 2H), 1.45 (s, 18H), 1.04 (m, 2H), 0.96 (m, 2H):

MS (+ve ESI): 759.7 (M+H)⁺.

EXAMPLE 48 Preparation of Compound 48 in Table1—2-{cyclopropyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyldihydrogen phosphate

An analogous reaction to that described in example 1 but starting withdi-tert-butyl2-{cyclopropyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethylphosphate (605 mg, 0.78 mmol) yielded the title compound (570 mg, 97%yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.91 (s, 1H), 7.71 (m, 1H), 7.64(s, 1H), 7.36 (s, 1H), 7.20 (m, 2H), 4.32 (m, 4H), 4.09 (s, 2H), 4.00(s, 3H), 3.62 (m, 2H), 3.51 (m, 2H), 3.00 (m, 1H), 2.39 (m, 2H), 1.11(m, 2H), 0.95 (m, 2H):

MS (+ve ESI): 665 (M+H)⁺.

di-tert-butyl2-{cyclopropyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethylphosphate, used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 1h, but    starting with    N-(2,3-difluorophenyl)-2-(2-(7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (1.25 g, 2.50 mmol) and cyclopropylamine (758 mg, 7.50 mmol) yielded    2-{2-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1,3-thiazol-5-yl}-N-(2,3-difluorophenyl)acetamide    (1.10 g, 77% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.91 (s, 1H), 7.71 (m, 1H), 7.65(s, 1H), 7.31 (s, 1H), 7.20 (m, 2H), 4.31 (m, 2H), 4.09 (s, 2H), 3.99(s, 3H), 3.85 (m, 1H), 3.81 (m, 1H), 3.44 (m, 4H), 2.96 (m, 1H), 2.37(m, 2H), 1.04 (m, 2H), 0.92 (m, 2H):

MS (+ve ESI): 585 (M+H)⁺.

-   b) An analogous reaction to that described in example 1i, but    starting with    2-{2-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1,3-thiazol-5-yl}-N-(2,3-difluorophenyl)acetamide    (670 mg, 1.15 mmol) yielded di-tert-butyl    2-{cyclopropyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl    phosphate (605 mg, 66% yield):

¹H-NMR (DMSO d₆, TFA): 9.08 (s, 1H), 7.91 (s, 1H), 7.71 (m, 1H), 7.65(s, 1H), 7.32 (s, 1H), 7.21 (m, 2H), 4.31 (m, 4H), 4.08 (s, 2H), 3.99(s, 3H), 3.63 (m, 2H), 3.50 (m, 2H), 2.99 (m, 1H), 2.38 (m, 2H), 1.03(m, 2H), 0.96 (m, 2H):

MS (+ve ESI): 777.6 (M+H)⁺.

EXAMPLE 49 Preparation of Compound 49 in Table2—(1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 1 but starting withdi(tert-butyl)(1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methylphosphate (350 mg, 0.45 mmol) yielded the title compound (190 mg, 64%yield):

¹H-NMR (DMSO d₆, CD₃COOD): 8.69 (s, 1H), 8.14 (s, 1H), 7.72 (m, 1H),7.37 (m, 2H), 7.18 (m, 2H), 4.55 (m, 2H), 3.99 (s, 2H), 3.97 (s, 3H),3.65 (m, 2H), 3.50 (m, 4H), 2.98 (m, 2H), 1.80 (m, 3H), 1.56 (m, 2H):

MS (+ve ESI): 665 (M+H).⁺

di(tert-butyl)(1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methylphosphate used as the starting material was obtained as follows:

-   a) A mixture of    N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide    (see example 1e) (6.00 g, 18.1 mmol), caesium carbonate (26 g, 82.2    mmol) and 1-bromo-2-chloroethane (2.51 ml, 30.2 mmol) in    acetonitrile (80 ml) was heated at reflux for 2 hours. The reaction    mixture was cooled, the solvent was evaporated in vacuo and the    residue taken up in water (200 ml). The aqueous phase was extracted    with dichloromethane (2×150 ml), the organic solution was washed    with brine (50 ml) and dried over magnesium sulphate. Solvent    evaporated in vacuo, trituration with diethyl ether and drying in    vacuo yielded    N′-(5-(2-chloroethoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (4.12 g, 81% yield) as a white solid:

MS (+ve ESI): 282 (M+H)⁺

MS (−ve ESI): 280 (M−H)⁻.

-   b) An analogous reaction to that described in example 42c, but    starting with    N-(2,3-difluorophenyl)-2-(2-((N-triphenylmethyl)amino)-1,3-thiazol-5-yl)acetamide    (1.65 g, 3.23 mmol) and    N′-(5-(2-chloroethoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (1.00 g, 3.55 mmol), yielded    N-(2,3-difluorophenyl)-2-(2-(7-(2-chloroethoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (820 mg, 51% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR DMSO d₆): 10.21 (s, 1H), 8.65 (s, 1H), 8.13 (s, 1H), 7.69 (m,1H), 7.37 (s, 1H), 7.29 (s, 1H), 7.17 (m, 2H), 4.43 (t, 2H), 4.03 (t,2H), 3.97 (s, 3H), 3.94 (s, 2H):

MS (+ve ESI): 505.9 (M+H)⁺

MS (−ve ESI): 503.9 (M−H)⁻.

-   c) An analogous reaction to that described in example 1h, but    starting with    N-(2,3-difluorophenyl)-2-(2-(7-(2-chloroethoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (680 mg, 1.35 mmol) and 4-(hydroxymethyl)piperidine (622 mg, 5.40    mmol) yielded    N-(2,3-difluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (565 mg, 72% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO d₆): 10.32 (s, 1H), 9.50 (m, 1H), 8.95 (s, 1H), 8.02 (m,1H), 7.70 (m, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.21 (m, 2H), 4.59 (t,2H), 4.06 (s, 2H), 4.00 (s, 3H), 3.68 (m, 5H), 3.29 (d, 2H), 3.12 (m,2H), 1.88 (m, 2H), 1.63 (m, 1H), 1.42 (m, 2H):

MS (+ve ESI): 585 (M+H)⁺

MS (−ve ESI): 583 (M−H)⁻.

-   d) An analogous reaction to that described in example 1i, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(2-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (565 mg, 0.97 mmol) yielded di(tert-butyl)    (1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyl    phosphate (350 mg, 47% yield):

MS (+ve ESI): 777 (M+H)⁺.

EXAMPLE 50 Preparation of Compound 50 in Table2—((2R)-1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)pyrrolidin-2-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 42e, but startingwithN-(2,3-difluorophenyl)-2-(2-((7-(2-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide(571 mg, 0.98 mmol) yielded di(tert-butyl)((2R)-1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)pyrrolidin-2-yl)methylphosphate. This material was not isolated but immediately subjected toan analogous reaction to that described in example 1 to yield the titlecompound as a dihydrochloride salt (110 mg, 64% yield over the twosteps):

¹H-NMR (DMSO d₆, CD₃COOD): 8.67 (s, 1H), 8.15 (s, 1H), 7.68 (m, 1H),7.31 (m, 2H), 7.15 (m, 2H), 4.48 (m, 2H), 4.10 (m, 1H), 3.98 (s, 3H),3.96 (s, 2H), 3.83 (m, 2H), 3.65 (m, 1H), 3.50 (m, 1H), 3.41 (m, 1H),3.03 (m, 1H), 2.05 (m, 2H), 1.82 (m, 2H):

MS (+ve ESI): 651 (M+H)⁺.

N-(2,3-difluorophenyl)-2-(2-((7-(2-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamideused as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 49c, but    starting with D-prolinol (0.54 ml, 5.40 mmol) yielded    N-(2,3-difluorophenyl)-2-(2-((7-(2-((2R)-2-(hydroxymethyl)pyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (580 mg, 75% yield) as a pale yellow solid after drying in vacuo:

¹H-NMR (DMSO d₆): 10.21 (s, 1H), 9.45 (m, 1H), 8.80 (s, 1H), 7.92 (m,1H), 7.58 (m, 1H), 7.45 (s, 1H), 7.28 (s, 1H), 7.11 (m, 2H), 4.46 (m,2H), 3.94 (s, 2H), 3.89 (s, 3H), 3.83 (m, 2H), 3.72 (m, 2H), 3.60 (m,2H), 3.24 (m, 2H), 1.99 (m, 2H), 1.78 (m, 1H), 1.65 (m, 2H);

MS (+ve ESI): 571 (M+H)⁺

MS (−ve ESI): 569 (M−H)⁻.

EXAMPLE 51 Preparation of Compound 51 in Table2—2-(4-(2-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)2-(4-(2-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)ethylphosphate (919 mg, 1.16 mmol) yielded the title compound (881 mg, 96%yield):

¹H-NMR (DMSO d₆): 10.50 (s, 1H), 9.00 (s, 1H), 7.90 (s, 1H), 7.75 (m,1H), 7.60 (s, 1H), 7.40 (s, 1H), 7.10-7.25 (m, 2H), 4.60-4.70 (m, 2H),4.20-4.30 (m, 2H), 4.10 (s, 2H), 4.01 (s, 3H), 3.45-3.80 (m, 8H),3.30-3.40 (m, 2H):

MS (+ve ESI): 680 (M+H)⁺.

di(tert-butyl)2-(4-(2-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)ethylphosphate used as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 49c, but    starting with N-(2-hydroxyethyl)piperazine (2.57 g, 19.8 mmol)    yielded    N-(2,3-difluorophenyl)-2-(2-((7-(2-(1-(4-(2-hydroxyethyl))piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (1.28 g, 54% yield):

¹H-NMR (DMSO d₆): 10.20 (s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 7.60-7.70(m, 1H), 7.40 (s, 1H), 7.25 (s, 1H), 7.13 (m, 2H), 4.30 (br s, 1H), 4.20(t, 2H), 3.98 (s, 2H), 3.95 (s, 3H), 3.40-3.50 (m, 2H), 2.75 (t, 2H)2.30-2.50 (m, 10H):

MS (+ve ESI): 600 (M+H)⁺

MS (−ve ESI): 598 (M−H)⁻.

-   b) An analogous reaction to that described in example 1i, but    starting with    N-(2,3-difluorophenyl)-2-(2-((7-(2-(1-(4-(2-hydroxyethyl))piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (1.18 g, 1.97 mmol) yielded di(tert-butyl)    2-(4-(2-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)ethyl    phosphate (919 mg, 59% yield):

¹H-NMR (DMSO d₆): 10.20 (s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 7.60-7.70(m, 1H), 7.40 (s, 1H), 7.25 (s, 1H), 7.10-7.20 (m, 2H), 4.20 (t, 2H),3.98 (s, 2H), 3.90 (s, 3H), 3.83 (m, 2H), 2.80 (t, 2H), 2.40-2.60 (m,8H), 1.40 (s, 18H):

MS (+ve ESI): 792 (M+H)⁺.

EXAMPLE 52 Preparation of Compound 52 in Table2—2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-2-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 1i, but starting withN-(3-fluorophenyl)-2-(2-((7-(2-(2-(2-hydroxyethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide(650 mg, 1.12 mmol) yielded di(tert-butyl)2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-2-yl)ethylphosphate which was not isolated. This material was not isolated butimmediately subjected to an analogous reaction to that described inexample 1 to yield the title compound (511 mg, 51% yield) as a paleyellow dihydrochloride salt:

¹H-NMR (DMSO-d₆): 10.80 (m, 2H), 9.06 (s, 1H), 7.90 (br s, 1H), 7.69 (m,2H), 7.42 (s, 1H), 7.38 (m, 2H), 6.92 (m, 1H), 4.65 (m, 2H), 4.03 (s,2H), 4.00 (s, 3H), 3.70 (m, 4H), 3.42 (m, 1H), 3.32 (m, 2H), 2.05 (m,2H), 1.84 (m, 2H), 1.72 (m, 2H), 1.51 (m, 2H):

MS (+ve ESI): 661 (M+H)⁺.

N-(3-fluorophenyl)-2-(2-((7-(2-(2-(2-hydroxyethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamideused as the starting material was obtained as follows:

-   a) Water (1 ml) and trifluoroacetic acid (10 ml) were added to    (2-((tert-butoxy-carbonyl)amino)-1,3-thiazol-5-yl)acetic acid (621    mg, 1.76 mol—for method see example 1n) and the reaction stirred at    ambient temperature for 45 minutes. Water (10 ml) was added and the    reaction stirred for a further 15 minutes before the solid (which    had precipitated) was collected by suction filtration, washed with    water (3×10 ml) and dried in vacuo to yield    N-(3-fluorophenyl)-2-amino-1,3-thiazol-5-ylacetamide (402 mg, 91%    yield):

¹H-NMR (DMSO d₆): 10.28 (br s, 1H), 7.58 (m, 1H), 7.30 (m, 2H), 6.88 (m,1H), 6.75 (s, 1H), 6.72 (br s, 2H), 2.12 (s, 2H):

MS (+ve ESI): 252 (M+H)⁺

MS (−ve ESI): 250 (M−H)⁻.

-   b) A mixture of N-(3-fluorophenyl)-2-amino-1,3-thiazol-5-ylacetamide    (9.99 g, 27.4 mmol) and    N′-(5-(2-chloroethoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide    (7.68 g, 27.4 mmol) in acetic acid (40 ml) was heated at reflux for    6 hours. The mixture was cooled and the solid product collected by    suction filtration, washed with acetic acid and then diethyl ether.    The solid was dissolved in dimethylacetamide (120 ml) and filtered.    Aqueous sodium bicarbonate solution (500 ml) was added slowly to the    filtrate and the solid product collected by suction filtration,    washed with water and dried to yield    N-(3-fluorophenyl)-2-(2-(7-(2-chloroethoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (7.69 g, 58% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 10.43 (br s, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.63 (m,1H), 7.33 (m, 3H), 7.17 (s, 1H), 6.89 (m, 1H), 4.42 (t, 2H), 4.05 (t,2H), 3.95 (s, 3H), 3.82 (s, 2H);

MS (+ve ESI): 488 (M+H)⁺

MS (−ve ESI): 486 (M−H)⁻.

-   c) An analogous reaction to that described in example 1h, but    starting with 2-(hydroxyethyl)piperidine (0.22 ml, 1.6 mmol) and    N-(3-fluorophenyl)-2-(2-(7-(2-chloroethoxy)-6-methoxyquinazolin-4-yl-amino-1,3-thiazol-5-yl)acetamide    (200 mg, 0.41 mmol) yielded    N-(3-fluorophenyl)-2-(2-((7-(2-(2-(2-hydroxyethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (19 mg, 8% yield):

¹H-NMR (DMSO d₆): 11.99 (m, 1H), 10.45 (br s, 1H), 8.68 (s, 1H), 8.12(br s, 1H), 7.63 (m, 1H), 7.38 (m, 3H), 7.30 (s, 1H), 6.90 (m, 1H), 4.24(t, 2H), 3.99 (s, 3H), 3.91 (s, 2H), 3.48 (m, 2H), 3.07 (m, 1H), 2.89(m, 2H), 2.55 (m, 2H), 1.80 (m, 1H), 1.55 (m, 5H), 1.31 (m, 2H):

MS (+ve ESI): 581 (M+H)⁺

MS (−ve ESI): 579 (M−H)⁻.

EXAMPLE 53 Preparation of Compound 53 in Table2—2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)ethyldihydrogen phosphate

An analogous reaction to that described in example 52, but starting withN-(3-fluorophenyl)-2-(2-((7-(2-(4-(2-hydroxyethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide(1.10 g, 1.89 mmol) yielded the title compound (676 mg, 54% yield) as apale yellow solid:

¹H-NMR (DMSO d₆): 11.05 (br s, 1H), 10.92 (s, 1H), 9.10 (s, 1H), 7.95(br s, 1H), 7.79 (m, 2H), 7.50 (s, 1H), 7.42 (m, 2H), 6.95 (m, 1H), 4.75(m, 2H), 4.10 (s, 2H), 4.05 (s, 3H), 3.95 (m, 2H), 3.70 (m, 4H), 3.18(m, 2H), 1.95 (m, 2H), 1.75 (m, 1H), 1.63 (m, 4H):

³¹P-NMR (¹H) (DMSO-d₆): −0.01 (s, 1P):

MS (+ve ESI): 661 (M+H)⁺.

N-(3-fluorophenyl)-2-(2-((7-(2-(4-(2-hydroxyethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamideused as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 52a, but    starting with 4-(2-hydroxyethyl)piperidine (0.22 ml, 1.6 mmol)    yielded    N-(3-fluorophenyl)-2-(2-((7-(2-(4-(2-hydroxyethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (52 mg, 22% yield):

¹H-NMR (DMSO d₆): 12.00 (m, 1H), 10.45 (br s, 1H), 8.68 (s, 1H), 8.12(br s, 1H), 7.63 (m, 1H), 7.37 (m, 3H), 7.29 (s, 1H), 6.91 (m, 1H), 4.30(m, 4H), 3.98 (s, 3H), 3.92 (s, 2H), 3.45 (q, 2H), 2.97 (m, 2H), 2.79(m, 2H), 2.06 (m, 2H), 1.65 (m, 2H), 1.37 (m, 2H), 1.18 (m, 2H):

MS (+ve ESI): 581 (M+H)⁺

MS (−ve ESI): 579 (M−H)⁻.

EXAMPLE 54 Preparation of Compound 54 in Table2—4-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)butyldihydrogen phosphate

An analogous reaction to that described in example 52, but starting with2-(2-((7-(2-(ethyl(4-hydroxybutyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide(602 mg, 1.06 mmol) yielded the title compound (85 mg, 15% yield) as apale yellow solid:

¹H-NMR (DMSO d₆): 10.65 (m, 2H), 8.97 (s, 1H), 7.85 (br s, 1H), 7.55 (m,2H), 7.30 (m, 3H), 6.85 (m, 1H), 4.57 (m, 2H), 3.95 (s, 2H), 3.93 (s,3H), 3.58 (m, 2H), 3.20 (m, 4H), 1.75 (m, 2H), 1.60 (m, 2H), 1.25 (t,3H):

³¹P-NMR (¹H) (DMSO-d₆): −0.12 (s, 1P)

MS (+ve ESI): 649 (M+H)⁺.

2-(2-((7-(2-(ethyl(4-hydroxybutyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamideused as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 52a, but    starting with 4-(ethylamino)-1-butanol (0.2 ml, 1.6 mmol) yielded    2-(2-((7-(2-(ethyl(4-hydroxybutyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (32 mg, 14% yield):

¹H-NMR (DMSO d₆): 11.96 (m, 1H), 10.45 (br s, 1H), 8.67 (s, 1H), 8.12(br s, 1H), 7.62 (m, 1H), 7.38 (m, 3H), 7.28 (s, 1H), 6.91 (m, 1H), 4.26(m, 2H), 3.98 (s, 3H), 3.90 (s, 2H), 3.42 (m, 2H), 2.95 (m, 2H), 2.64(m, 4H), 1.48 (m, 4H), 1.03 (t, 3H):

MS (+ve ESI): 569 (M+H)⁺

MS (−ve ESI): 567 (M−H)⁻.

EXAMPLE 55 Preparation of Compound 55 in Table2—2-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)ethyldihydrogen phosphate

An analogous reaction to that described in example 52, but starting with2-(2-((7-(2-(ethyl(2-hydroxyethyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide(710 mg, 1.31 mmol) yielded the title compound (616 mg, 76% yield) as apale yellow solid:

¹H-NMR (DMSO d₆): 10.90 (s, 1H), 8.99 (s, 1H), 7.86 (br s, 1H), 7.65 (d,1H), 7.60 (s, 1H), 7.41 (m, 3H), 6.90 (m, 1H), 4.70 (m, 2H), 4.33 (m,2H), 4.05 (s, 2H), 3.97 (s, 3H), 3.75 (m, 2H), 3.55 (m, 2H), 3.38 (q,2H), 1.37 (t, 3H):

³¹P-NMR (¹H) (DMSO d₆): −0.15 (s, 1P)

MS (+ve ESI): 621 (M+H)⁺.

2-(2-((7-(2-(ethyl(2-hydroxyethyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamideused as the starting material was obtained as follows:

-   a) An analogous reaction to that described in example 52a, but    starting with 2-(ethylamino)-1-ethanol (0.15 ml, 1.6 mmol) yielded    2-(2-((7-(2-(ethyl(2-hydroxyethyl)amino)ethoxy)-6-methoxyquinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (41 mg, 19% yield):

¹H-NMR (DMSO d₆): 11.98 (m, 1H), 10.45 (br s, 1H), 8.67 (s, 1H), 8.12(br s, 1H), 7.62 (m, 1H), 7.37 (m, 3H), 7.27 (s, 1H), 6.91 (m, 1H), 4.29(t, 1H), 4.22 (t, 2H), 3.97 (s, 3H), 3.90 (s, 2H), 3.48 (q, 2H), 2.94(t, 2H), 2.65 (m, 4H), 1.01 (t, 3H):

MS (+ve ESI): 541 (M+H)⁺

MS (−ve ESI): 539 (M−H)⁻.

EXAMPLE 56 Preparation of Compound 56 in Table3—(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi(tert-butyl)(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate (640 mg, 0.86 mmol) yielded the title compound (353 mg, 55%yield), as the dihydrochloride salt, as a pale yellow solid:

¹H-NMR (DMSO d₆): 10.87 (s, 1H), 10.58 (s, 1H), 9.04 (s, 1H), 8.42 (d,1H), 7.65 (m, 2H), 736 (m, 4H), 6.91 (m, 1H), 4.28 (m, 2H), 4.05 (s,2H), 3.72 (t, 2H), 3.55 (d, 2H), 3.23 (m, 3H), 2.95 (m, 2H), 2.33 (m,2H), 1.85 (m, 2H), 1.61 (m, 2H):

³¹P-NMR(¹H) (DMSO d₆): 0.05 (1P):

MS (−ve ESI): 629 (M−H)⁻

MS (+ve ESI): 631 (M+H)⁺.

di(tert-butyl)(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methylphosphate used as the starting material was obtained as follows:

-   a) 2-Amino-4-fluorobenzoic acid (15 g, 96.7 mmol) was dissolved in    2-methoxyethanol (97 ml) and formamidine acetate (20.13 g, 193.4    mmol) was added before the mixture was heated at reflux for 18    hours. The reaction was cooled, concentrated and the residue stirred    in 0.01 N aqueous ammonium hydroxide solution (250 ml) for 1 hour.    The suspension was filtered, washed with water and dried over    phosphorus pentoxide to yield 7-fluoroquinazolin-4(3H)-one as an    off-white solid (10.35 g, 65% yield):

¹H-NMR (DMSO d₆): 12.32 (br s, 1H), 8.19 (dd, 1H), 8.14 (s, 1H), 7.45(dd, 1H), 7.39 (m, 1H):

MS (+ve ESI): 165 (M+H)⁺

MS (−ve ESI): 163 (M−H)⁻.

-   b) Sodium hydride (14.6 g, 365 mmol) was added at 0° C. to a    solution of 1,3-propanediol (27.8 g, 365.5 mmol) in    dimethylformamide (70 ml). 7-Fluoroquinazolin-4(3H)-one (10 g, 60.9    mmol) was added portionwise and the reaction mixture heated at 60°    C., then at 110° C. for 3 hours. The reaction was cooled to 0° C.,    quenched with water (280 ml) and acidified to pH 5.9. The resulting    suspension was filtered, washed with water then diethyl ether and    dried over phosphorus pentoxide to yield    7-(3-hydroxypropoxy)quinazolin-4(3H)-one as a white powder (12.41 g,    92% yield):

¹H-NMR (DMSO d₆): 11.90 (br s, 1H), 8.04 (s, 1H), 8.00 (d, 1H), 7.10 (m,2H), 4.17 (t, 2H), 3.58 (t, 2H), 1.92 (m, 2H):

MS (+ve ESI): 221 (M+H)⁺.

-   c) Dimethylformamide (1 ml) was added dropwise to a mixture of    thionyl chloride (100 ml, 137 mmol) and    7-(3-hydroxypropoxy)quinazolin-4(3H)-one (10.5 g, 47.7 mmol) and the    reaction mixture heated to 85° C. for 1 hour. The mixture was cooled    to ambient temperature, diluted with toluene and evaporated to    dryness. This was repeated until all thionyl chloride was removed.    The residue was dissolved in dichloromethane and washed with a    saturated sodium bicarbonate solution. The aqueous layer was    extracted with dichloromethane. The organics were combined, dried    (magnesium sulphate) and concentrated to leave a yellow solid.    Trituration with diethyl ether removed a less soluble impurity and    the ether filtrate was concentrated to yield    4-chloro-7-(3-chloropropoxy)quinazoline as an off-white solid (8.5    g, 70% yield):

¹H-NMR (DMSO d₆): 13.25 (br s, 1H), 8.34 (s, 1H), 8.06 (d, 1H), 7.17 (m,2H), 4.21 (t, 2H), 3.83 (t, 2H), 2.23 (m, 2H):

MS (+ve ESI): 257, 259 (M+H)⁺.

-   d) Sodium tert-butoxide (76.5 mg, 0.80 mmol) was added to a    suspension of    2-(2-amino-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide (100 mg,    0.398 mmol) and 4-chloro-7-(3-chloropropoxy)quinazoline (102 mg,    0.398 mmol) in dioxan (1 ml) and the reaction heated at reflux for 7    hours. The reaction was cooled to ambient temperature and dioxan    (1 ml) and water (8 ml) were added before the pH was adjusted to <8    by addition of a few drops of 1.0 N hydrochloric acid. Collection of    the resultant solid by suction filtration followed by prolonged    drying in vacuo yielded    2-(2-((7-(3-chloropropoxy)quinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (139 mg, 74% yield) as a brown powdery solid:

¹H-NMR (DMSO-d₆): 12.12 (br s, 1H), 10.47 (s, 1H), 8.73 (s, 1H), 8.63(s, 1H), 7.63 (d, 1H), 7.18-7.44 (m, 5H), 6.91 (dd, 1H), 4.29 (t, 2H),3.88 (s, 2H), 3.83 (t, 2H), 2.25 (m, 2H):

MS (−ve ESI): 470, 472 (M−H)⁻

MS (+ve ESI): 472, 474 (M+H)⁺.

-   e) An analogous reaction to that described in example 1h, but    starting with    2-(2-((7-(3-chloropropoxy)quinazolin-4-yl)amino)-1,3-thiazol-5-yl)-N-(3-fluorophenyl)acetamide    (1.50 g, 3.18 mol) and piperidin-4-ylmethanol (1.28 g, 11.1 mmol)    yielded    N-(3-fluorophenyl)-2-(2-((7-(3-(4-hydroxymethyl)piperidin-1-yl)propoxy)quinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (580 mg, 33% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 12.00 (br s, 1H), 10.47 (s, 1H), 8.71 (s, 1H), 8.60(d, 1H), 7.62 (d, 1H), 7.14-7.46 (m, 5H), 6.86 (m, 1H), 4.37 (s, 1H),4.20 (s, 2H), 3.89 (s, 2H), 3.29 (s, 2H), 2.95 (m, 2H), 1.80-2.13 (m,5H), 1.66 (m, 2H), 1.37 (s, 1H), 1.17 (m, 2H):

MS (−ve ESI): 549 (M−H)⁻

MS (+ve ESI): 551 (M+H)⁺.

-   f) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-(2-((7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)quinazolin-4-yl)amino)-1,3-thiazol-5-yl)acetamide    (518 mg, 0.94 mmol) yielded di(tert-butyl)    (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl    phosphate (651 mg, 93% yield) as an orange oil:

¹H-NMR (DMSO d₆): 12.11 (br s, 1H), 10.43 (s, 1H), 8.72 (s, 1H), 8.60(d, 1H), 7.62 (d, 1H), 7.19-7.40 (m, 5H), 6.86 (dd, 1H), 4.20 (t, 2H),3.90 (s, 2H), 3.70 (t, 2H), 3.16 (m, 1H), 2.90 (m, 2H), 2.47 (m, 2H),1.90 (m, 2H), 1.50-1.68 (m, 4H), 1.40 (s, 18H), 1.24 (m, 2H):

³¹P-NMR(¹H) (DMSO d₆): −8.55 (1P):

MS (−ve ESI): 741 (M−H)⁻

MS (+ve ESI): 743 (M+H)⁺.

EXAMPLE 57 Preparation of Compound 57 in Table4—2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyldihydrogen phosphate

An analogous reaction to that described in example 1, but starting withdi-tert-butyl2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethylphosphate (145 mg, 0.19 mmol) yielded the title compound (117 mg, 85%yield), as the dihydrochloride salt, as a pale yellow solid:

¹H-NMR (DMSO d₆): 10.70 (s, 1H), 10.50 (br s, 1H), 9.04 (s, 1H), 7.90(s, 1H), 7.50-7.60 (m, 2H), 7.40 (s, 1H), 7.20-7.30 (m, 2H), 6.80-6.90(m, 1H), 4.30-4.40 (m, 2H), 4.07 (m, 2H), 4.00 (s, 2H), 3.98 (s, 3H),3.60-3.70 (m, 2H), 3.30-3.40 (m, 2H), 3.00-3.20 (m, 2H), 2.10-2.20 (m,1H), 2.00 (d, 2H), 1.80-1.90 (m, 2H):

³¹P-NMR(¹H) (DMSO d₆): 0.30 (1P):

MS (+ve ESI): 647 (M+H)⁺.

di-tert-butyl2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethylphosphate, used as the starting material, was obtained as follows:

-   a) A solution of di-tert-butyl dicarbonate (41.7 g, 0.19 mol) in    ethyl acetate (75 ml) was added dropwise to a solution of ethyl    4-piperidinylcarboxylate (30 g, 0.19 mol) in ethyl acetate (150 ml)    while maintaining the temperature in the range 0-5° C. The reaction    was stirred at ambient temperature for 48 hours, poured onto water    (300 ml) and the organic layer was separated and washed with i)    water (200 ml), ii) 0.1N aqueous hydrochloric acid (200 ml), iii)    saturated sodium hydrogen carbonate (200 ml) and iv) brine (200 ml).    Evaporation and drying in vacuo yielded ethyl    (1-tert-butyloxycarbonylpiperidin-4-yl)carboxylate (48 g, 98% yield)    as a white solid:

¹H NMR (CDCl₃): 4.15 (q, 2H), 3.91-4.10 (s, 2H), 2.70-2.95 (t, 2H),2.35-2.50 (m, 1H), 1.80-2.00 (d, 2H), 1.55-1.70 (m, 2H), 1.45 (s, 9H),1.25 (t, 3H).

-   b) A solution of 1.0N lithium aluminium hydride in tetrahydrofuran    (133 ml, 0.133 mol) was added dropwise to a solution of ethyl    (1-tert-butyloxycarbonylpiperidin-4-yl)carboxylate (48 g, 0.19 mol)    in dry tetrahydrofuran (180 ml) at 0° C. The reaction was stirred at    0° C. for 2 hours, water (30 ml) and 2.0N sodium hydroxide (10 ml)    were added and the precipitate was filtered through diatomaceous    earth and washed with ethyl acetate. The filtrate was washed with    water and brine before being evaporated to yield    4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (36.3 g, 89%    yield) as a white solid:

¹H NMR (CDCl₃): 4.10 (s, 2H), 3.40-3.60 (t, 2H), 2.60-2.80 (t, 2H),1.60-1.80 (m, 2H), 1.35-1.55 (m, 10H), 1.05-1.20 (m, 2H):

MS (+ve EI): 215 (M+H)⁺.

-   c) 1,4-Diazabicyclo[2.2.2]octane (42.4 g, 0.378 mol) was added to a    solution of 4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (52.5    g, 0.244 mol) in tert-butyl methyl ether (525 ml) and the reaction    stirred at ambient temperature for 15 minutes. The reaction was    cooled to 5° C. and a solution of 4-toluenesulphonyl chloride (62.8    g, 0.33 mmol) in tert-butyl methyl ether (525 ml) was added dropwise    over 2 hours while maintaining the temperature at 0° C. The reaction    was stirred at ambient temperature for 1 hour, isohexane was added    and the resultant precipitate was collected by suction filtration.    Solvent evaporation in vacuo afforded a solid which was dissolved in    diethyl ether (250 ml) and washed successively with 0.5 N aqueous    hydrochloric acid (2×500 ml), water, saturated sodium hydrogen    carbonate and brine. Solvent evaporation and drying in vacuo yielded    4-(4-methylphenylsulphonyloxy-methyl)-1-tert-butyloxy-carbonylpiperidine    (76.7 g, 85% yield) as a white solid:

¹H NMR (CDCl₃): 7.80 (d, 2H), 7.35(d, 2H), 4.00-4.20 (s, 2H), 3.85 (d,1H), 2.55-2.75 (m, 2H), 2.45 (s, 3H), 1.75-1.90 (m, 2H), 1.65 (d, 2H),1.45 (s, 9H), 1.00-1.20 (m, 2H):

MS (+ve ESI): 392 (M+Na)⁺.

-   d) N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide    (2.46 g, 7.42 mmol), tert-butyl    4-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidin-1-ylcarboxylate    (3.00 g, 8.90 mmol) and caesium carbonate (6.00 g, 18.6 mmol) were    combined in acetontirile (150 ml) and the reaction heated at reflux    for 18 hours. The solvents were removed in vacuo, the residue was    stirred with saturated sodium hydrogen carbonate solution and then    extracted with ethyl actetae (3×75 ml). Solvent evaporation in vacuo    yielded tert-butyl    4-[(4-cyano-5-{[(1E)-(dimethylamino)methylene]amino}-2-methoxyphenoxy)methyl]piperidin-1-ylcarboxylate,    as a brown oil, which was not characterised but taken up in acetic    acid (15 ml) and heated at 145° C. for 4 hours with tert-butyl    (5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)carbamate    (2.60 g, 7.42 mmol). The reaction was cooled, concentrated in vacuo,    taken up in methanol and neutralised by addition of excess saturated    aqueous sodium hydrogen carbonate solution. The water was decanted    off and the brown gum was taken up in methanol and purified by flash    chromatography on silica gel, eluting with 10-20% methanol in    dichloromethane (with 1% ammonia added). Solvent evalporation in    vacuo followed by trituartion with deithyl ether and drying in vacuo    yielded    N-(3-fluorophenyl)-2-(2-{[6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl]amino}-1,3-thiazol-5-yl)acetamide    (1.92 g, 49% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 10.42 (s, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 7.55-7.65(m, 1H), 7.25-7.40 (m, 3H), 7.20 (s, 1H), 6.80-6.90 (m, 1H), 4.00 (d,2H), 3.98 (s, 3H), 3.80 (s, 2H), 2.90-3.00 (m, 2H), 2.50-2.60 (m, 2H),1.80-2.00 (m, 1H), 1.65-1.75 (m, 2H), 1.15-1.30 (m, 2H):

MS (−ve ESI): 521 (M−H)⁻

MS (+ve ESI): 523 (M+H)⁺.

-   e) Sodium tri(acetoxy)borohydride (814 mg), was added to a stirred    solution of    N-(3-fluorophenyl)-2-(2-{[6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl]amino}-1,3-thiazol-5-yl)acetamide    (1.00 g, 1.92 mmol), {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde    (1.67 g, 9.58 mmol) and acetic acid (0.88 ml, 15.4 mmol) in a    mixture of tetrahydrofuran (15 ml) and methanol (15 ml) and the    reaction stirred for 18 hours at ambient temperature. The volatiles    were removed in vacuo, the residue was basified by washing with    saturated aquoeus sodium hydrogen carbonate solution and the aqueous    layer was extracted with dichloromethane (3×50 ml). Purification by    flash chromatography on silica gel, eluting with    dichloromethane:methanol (90:10) to dichloromethane:methanol:7.0 N    aqueous ammonia (19:80:1) yielded    2-{2-[(7-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-4-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-1,3-thiazol-5-yl}-N-(3-fluorophenyl)acetamide    (302 mg, 23% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 10.38 (s, 1H), 8.60 (s, 1H), 8.05 (br s, 1H), 7.58 (m,1H), 7.35 (s, 1H), 7.20-7.30 (m, 2H), 7.15 (s, 1H), 6.80-6.90 (m, 1H),3.98 (m, 2H), 3.90 (s, 3H), 3.80 (s, 2H), 3.60 (t, 2H), 2.80-2.90 (m,2H), 2.37 (m, 2H), 1.90-2.10 (m, 2H), 1.65-1.80 (m, 3H), 1.20-1.40 (m,2H), 0.80 (s, 9H), 0.10 (s, 6H):

MS (−ve ESI): 679 (M−H)⁻

MS (+ve ESI): 680 (M+H)⁺.

-   f) Tetrabutylammonium fluoride (3.75 ml of a 1.0 N solution in    tetrahydrofuran, 3.75 mmol) was added to a stirred solution of    2-{2-[(7-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethyl)piperidin-4-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-1,3-thiazol-5-yl}-N-(3-fluorophenyl)acetamide    (511 mg, 0.75 mmol) in tetrahydrofuran (5 ml) and the reaction    stirred for 3 hours at ambient temperature. The volatiles were    removed in vacuo and the reaction was diluted by addition of    dimethylsulphoxide (10.5 ml), acetonitrile (3 ml) and water (1.5    ml). The reaction was acidified with trifluoroacetic acid and the    product purified by reverse phase HPLC. Concentration of the    fraction sin vacuo, followed by treatment with solid sodium    carbonate, caused precipitation of a yellow solid which was    collected by suction filtration. Extended drying in vacuo yielded    N-(3-fluorophenyl)-2-{2-[(7-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-1,3-thiazol-5-yl}acetamide    (318 mg, 75% yield) as a yellow solid:

¹H-NMR (DMSO d₆): 10.42 (s, 1H), 8.60 (s, 1H), 8.00 (s, 1H), 7.57 (m,1H), 7.25-7.35 (m, 3H), 7.20 (s, 1H), 6.80-6.90 (m, 1H), 4.35 (br s,1H), 4.00 (d, 2H), 3.95 (s, 3H), 3.80 (s, 2H), 3.40-3.50 (m, 2H),2.80-2.90 (m, 2H), 2.40 (t, 2H), 1.90-2.00 (m, 2H), 1.70-1.80 (m, 3H),1.20-1.30 (m, 2H):

MS (−ve ESI): 565 (M−H)⁻

MS (+ve ESI): 567 (M+H)⁺.

-   g) An analogous reaction to that described in example 1i, but    starting with    N-(3-fluorophenyl)-2-{2-[(7-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-1,3-thiazol-5-yl}acetamide    (290 mg, 0.51 mmol) yielded di-tert-butyl    2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl    phosphate (145 mg, 37% yield) as a yellow solid:

¹H-NMR (DMSO d₆): 10.42 (s, 1H), 8.60 (s, 1H), 8.20 (s, 1H), 7.57 (m,1H), 7.40 (s, 1H), 7.33 (m, 2H), 7.20 (s, 1H), 6.80-6.90 (m, 1H), 4.00(d, 2H), 3.98 (s, 3H), 3.92 (m, 2H), 3.87 (s, 2H), 3.60-3.70 (m, 2H),2.90-3.00 (m, 2H), 2.57 (m, 2H), 2.00-2.20 (m, 2H), 1.88 (m, 3H), 1.40(s, 18H), 1.30-1.40 (m, 2H):

MS (+ve ESI): 759 (M+H)⁺.

1. A compound of formula (I):

wherein A is 5-membered heteroaryl containing a sulphur atom andoptionally containing one or more nitrogen atoms; X is O, S, S(O), S(O)₂or NR¹⁴; m is 0, 1, 2 or 3; Z is a group selected from —NR¹R²,phosphonooxy, C₃₋₆cycloalkyl which C₃₋₆cycloalkyl is substituted byphosphonooxy or C₁₋₄alkyl substituted by phosphonooxy, and a 4- to7-membered ring linked via a carbon atom, containing a nitrogen atom andoptionally containing a further nitrogen atom which ring may besaturated, unsaturated or partially saturated, wherein the ring issubstituted on carbon or nitrogen by phosphonooxy or C₁₋₄alkylsubstituted by phosphonooxy and wherein the ring is optionally furthersubstituted on carbon or nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups;R¹ is a group selected from —COR⁸, —CONR⁸R⁹ and C₁₋₆alkyl whichC₁₋₆alkyl is substituted by phosphonooxy and optionally furthersubstituted by 1 or 2 halo or methoxy groups; R² is a group selectedfrom hydrogen, —COR¹⁰, —CONR¹⁰R¹¹ and C₁₋₆alkyl which C₁₋₆alkyl isoptionally substituted by 1, 2, or 3 halo or C₁₋₄alkoxy groups or—S(O)_(p)R¹¹ (where p is 0, 1 or 2) or phosphonooxy, or R² is a groupselected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkylC₁₋₄alkyl; or R¹ and R² together with the nitrogen towhich they are attached form a 4- to 7-membered ring optionallycontaining a further nitrogen atom which ring may be saturated,unsaturated or partially saturated, wherein the ring is substituted oncarbon or nitrogen, by a group selected from phosphonooxy and C₁₋₄alkylwhich C₁₋₄alkyl is substituted by phosphonooxy or —NR⁸R⁹, and where thering is optionally further substituted on carbon or nitrogen, by 1, 2 or3 halo or C₁₋₄alkyl groups; R³ is a group selected from hydrogen, halo,cyano, nitro, C₁₋₆alkoxy, C₁₋₆alkyl, —OR¹², —CHR¹²R¹³, —OC(O)R¹²,—C(O)R¹², —NR¹²C(O)R¹³, —C(O)NR¹²R¹³, —NR¹²SO₂R¹³ and —NR¹²R¹³; R⁴ ishydrogen or a group selected from C₁₋₄alkyl, heteroaryl,heteroarylC₁₋₄alkyl, aryl and arylC₁₋₄alkyl which group is optionallysubstituted by 1, 2 or 3 substituents selected from halo, methyl, ethyl,cyclopropyl and ethynyl; R⁵ is a group selected from hydrogen,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkylC₁₋₄alkyl; R⁶ and R⁷ are independently selected fromhydrogen, halo, C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy and C₁₋₄alkoxy; R⁸ isC₁₋₄alkyl substituted by phosphonooxy and optionally further substitutedby 1 or 2 halo or methoxy groups; R⁹ is a group selected from hydrogenor C₁₋₄alkyl; R¹⁰ is a group selected from hydrogen and C₁₋₄alkyl whichC₁₋₄alkyl is optionally substituted by halo, C₁₋₄alkoxy, S(O)_(q) (whereq is 0, 1 or 2) or phosphonooxy; R¹¹, R¹², R¹³ and R¹⁴ are independentlyselected from hydrogen, C₁₋₄alkyl or heterocyclyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein A isa group of formula (a), (b), (c), (d), (e) or (f):

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the (CR⁶R⁷) group of formula (I); or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 2 wherein A is a group of formula (a) as defined in claim 2; or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1 wherein X is NH; or a pharmaceutically acceptable salt thereof.5. A compound according to claim 1 wherein Z is —NR¹R² or a 4- to7-membered saturated ring linked via a carbon atom, containing anitrogen atom, which ring is substituted on carbon or nitrogen byphosphonooxy or C₁₋₄alkyl substituted by phosphonooxy; or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1 wherein R¹ is C₁₋₅alkyl substituted by phosphonooxy and R² ishydrogen, 2-propynyl, methyl, ethyl, butyl, cyclopropyl, where thelatter four groups are optionally substituted by fluoro, chloro, methoxyand ethoxy; or R¹ and R² together with the nitrogen to which they areattached form a saturated 5- to 6-membered ring optionally containing afurther nitrogen atom wherein the ring is substituted on carbon onnitrogen by a group selected from phosphonooxy, and C₁₋₄alkyl whichC₁₋₄alkyl is substituted by phosphonooxy or —NR⁸R⁹ and where the ring isoptionally further substituted on carbon or nitrogen, by 1 or 2C₁₋₄alkyl groups; or a pharmaceutically acceptable salt thereof.
 7. Acompound according to claim 1 wherein R³ is C₁₋₄alkoxy or hydrogen; or apharmaceutically acceptable salt thereof.
 8. A compound according toclaim 1 wherein R⁴ is phenyl optionally substituted by 1 or 2 of fluoroor chloro; or a pharmaceutically acceptable salt thereof.
 9. A compoundselected from:(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyldihydrogen phosphate;((2R)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;2-(4-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyldihydrogen phosphate;1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-3-yldihydrogen phosphate;1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-3-yldihydrogen phosphate;2-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate;((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;2-(ethyl(((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyldihydrogen phosphate;1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yldihydrogen phosphate;2-((((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl)amino)ethyldihydrogen phosphate;2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate;3-(ethyl(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)propyldihydrogen phosphate;2-((2-fluoroethyl)(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate;2-(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyldihydrogen phosphate;2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(2-methoxyethyl)amino)ethyldihydrogen phosphate;2-((2S)-1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)ethyldihydrogen phosphate;2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyldihydrogen phosphate;((2R)-1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;2-(1-(3-((4-((5-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)ethyldihydrogen phosphate;2-(4-(3-((4-((5-(2-(3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyldihydrogen phosphate;2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyldihydrogen phosphate;((2S)-1-(3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;(1R)-2-((3-((4-((5-(2-((3,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-1-methylethyldihydrogen phosphate;((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;((2S)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyldihydrogen phosphate;(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl dihydrogen phosphate;((2R)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;((2S)-1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;2-(ethyl(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate;2-(1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyldihydrogen phosphate;((2R)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;((2S)-1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(methyl)amino)ethyldihydrogen phosphate;2-(1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyldihydrogen phosphate;2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyldihydrogen phosphate;1-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-ylmethyldihydrogen phosphate;2-(4-(3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxy-quinazolin-7-yl)oxy)propyl)piperazin-1-yl)ethyldihydrogen phosphate;3-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-3-methylbutyldihydrogen phosphate;2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)-2-methylpropyldihydrogen phosphate;2-((3-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)amino)ethyldihydrogen phosphate;((2R)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;((2S)-1-(3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;2-((3-((4-((5-(2-((2,5-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyldihydrogen phosphate;((2S)-1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyldihydrogen phosphate;2-(1-(3-((4-((5-(2-((2,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-2-yl)ethyldihydrogen phosphate;2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyldihydrogen phosphate;2-{cyclopropyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyldihydrogen phosphate;(1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)methyldihydrogen phosphate;((2R)-1-(2-((4-((5-(2-((2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)pyrrolidin-2-yl)methyldihydrogen phosphate;2-(4-(2-((4-((5-(2-(2,3-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazin-1-yl)ethyldihydrogen phosphate;2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-2-yl)ethyldihydrogen phosphate;2-(1-(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperidin-4-yl)ethyldihydrogen phosphate;4-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)butyldihydrogen phosphate;2-(ethyl(2-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)ethyl)amino)ethyldihydrogen phosphate;(1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyldihydrogen phosphate; and2-{4-[({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyldihydrogen phosphate; or a pharmaceutically acceptable salt thereof. 10.A pharmaceutical composition comprising a compound according to claim 1or a pharmaceutically acceptable salt thereof in association with apharmaceutically acceptable diluent or carrier. 11.-14. (canceled)
 15. Amethod of treating a human suffering from a disease in which theinhibition of one or more Aurora kinases is beneficial to the treatment,comprising the steps of administering to a person in need thereof atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 16. A method of treating ahuman suffering from colorectal, breast, lung, prostate, pancreatic orbladder and renal cancer or leukemias or lymphomas, comprising the stepsof administering to a person in need thereof a therapeutically effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 17. A process for the preparation of a compoundof formula (I) according to claim 1 or a pharmaceutically acceptablesalt thereof, which process comprises converting a compound of formula(II) into a compound of formula (I) by phosphorylation of an appropriatehydroxy group:

where A, X, m, R³, R⁴, R⁵, R⁶, R⁷ and R⁹ are as defined for formula (I);Z′ is a group selected from —NR^(1′)R^(2′), hydroxy, C₃₋₆cycloalkylwhich C₃₋₆cycloalkyl is substituted by hydroxy or C₁₋₄alkyl substitutedby hydroxy, and a 4- to 7-membered ring linked via a carbon atom,containing a nitrogen atom and optionally containing a further nitrogenatom which ring may be saturated, unsaturated or partially saturated,wherein the ring is substituted on carbon or nitrogen by hydroxy orC₁₋₄alkyl substituted by hydroxy, and wherein the ring is optionallyfurther substituted by 1, 2 or 3 halo or C₁₋₄alkyl groups; and R^(1′) is—COR^(8′), —CONR^(8′)R⁹ or C₁₋₆alkyl which C₁₋₆alkyl is substituted byhydroxy and optionally further substituted on carbon or nitrogen by 1 or2 halo or methoxy groups; R^(2′) is hydrogen, —COR¹⁰, —CONR¹⁰R¹¹,C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1, 2, or 3 haloor C₁₋₄alkoxy groups or —S(O)_(p)R¹¹ (where p is 0, 1 or 2) or hydroxy,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl; orR^(1′) and R^(2′) together with the nitrogen to which they are attachedform a 4- to 7-membered ring optionally containing a further nitrogenatom which may be saturated, unsaturated or partially saturated, whereinthe ring is substituted on carbon or nitrogen by a group selected fromhydroxy and C₁₋₄alkyl substituted by hydroxy or —NR^(8′)R⁹ and where thering is optionally further substituted on carbon or nitrogen by 1, 2 or3 halo or C₁₋₄alkyl groups; and where R^(8′) is C₁₋₄alkyl substituted byhydroxy and optionally further substituted by 1 or 2 halo or methoxygroups: and thereafter if necessary: i) converting a compound of theformula (I) into another compound of the formula (I); and/or ii)removing any protecting groups; and/or iii) forming a pharmaceuticallyacceptable salt thereof.
 18. The method according to claim 15 whereinAurora kinase is Aurora-A kinase or Aurora-B kinase.
 19. A compoundaccording to claim 1 wherein A is a group of formula (a), (b), (c), (d),(e) or (f):

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the (CR⁶R⁷) group of formula (I); X is NH;m is 0, 1, 2 or 3; Z is —NR¹R² or a 4- to 7-membered saturated ringlinked via a carbon atom, containing a nitrogen atom, which ring issubstituted on carbon or nitrogen by phosphonooxy or C₁₋₄alkylsubstituted by phosphonooxy; R¹ is C₁₋₅alkyl substituted by phosphonooxyand R² is hydrogen, 2-propynyl, methyl, ethyl, butyl, cyclopropyl, wherethe latter four groups are optionally substituted by fluoro, chloro,methoxy and ethoxy; or R¹ and R² together with the nitrogen to whichthey are attached form a saturated 5- to 6-membered ring optionallycontaining a further nitrogen atom wherein the ring is substituted oncarbon on nitrogen by a group selected from phosphonooxy, and C₁₋₄alkylwhich C₁₋₄alkyl is substituted by phosphonooxy or —NR⁸R⁹ and where thering is optionally further substituted on carbon or nitrogen, by 1 or 2C₁₋₄alkyl groups; R³ is C₁₋₄alkoxy or hydrogen; R⁴ is phenyl optionallysubstituted by 1 or 2 of fluoro or chloro; R⁵ is a group selected fromhydrogen, C₁₋₄alkyl, C₂₋₄alkynyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkylC₁₋₄alkyl; R⁶ and R⁷ are independently selected fromhydrogen, halo, C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy and C₁₋₄alkoxy; R⁸ isC₁₋₄alkyl substituted by phosphonooxy and optionally further substitutedby 1 or 2 halo or methoxy groups; R⁹ is a group selected from hydrogenor C₁₋₄alkyl; or a Pharmaceutically acceptable salt thereof.
 20. Acompound according to claim 1 wherein: A is a group of formula (a)

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the (CR⁶R⁷) group of formula (I); X is NH;m is 0, 1 or 2; Z is —NR¹R² or a 4- to 7-membered saturated ring linkedvia a carbon atom, containing a nitrogen atom, which ring is substitutedon carbon or nitrogen by Phosphonooxy or C₁₋₄alkyl substituted byphosphonooxy; R¹ is C₁₋₅alkyl substituted by phosphonooxy; R² is a groupselected from hydrogen and C₁₋₄alkyl which C₁₋₄alkyl is optionallysubstituted by halo or C₁₋₄alkoxy, or R² is a group selected fromC₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₄alkyl; R³ is C₁₋₄alkoxy or hydrogen;R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; R⁶ ishydrogen or methyl; and R⁶ and R⁷ are independently hydrogen, fluoro,chloro or methyl; or a Pharmaceutically acceptable salt thereof.
 21. Acompound according to claim 1 wherein: A is a group of formula (a)

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the (CR⁶R⁷) group of formula (I); X is NH;m is 0, 1 or 2; Z is —NR¹R² or a 4- to 7-membered saturated ring linkedvia a carbon atom, containing a nitrogen atom, which ring is substitutedon carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted byphosphonooxy; R¹ is C₁₋₅alkyl substituted by phosphonooxy; R² ishydrogen, 2-propynyl, methyl, ethyl, butyl, cyclopropyl, where thelatter four groups are optionally substituted by fluoro, chloro, methoxyand ethoxy; R³ is hydrogen; R⁴ is phenyl optionally substituted by 1 or2 of fluoro or chloro; R⁵ is hydrogen or methyl; and R⁶ and R⁷ areindependently hydrogen, fluoro, chloro or methyl; or a pharmaceuticallyacceptable salt thereof.
 22. A compound according to claim 1 wherein: Ais a group of formula (a)

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the (CR⁶R⁷) group of formula (I); X is NH;m is 1, 2 or 3; Z is —NR¹R² or a 4- to 7-membered saturated ring linkedvia a carbon atom, containing a nitrogen atom, which ring is substitutedon carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted byphosphonooxy; R¹ and R² together with the nitrogen to which they areattached form a saturated 5- to 6-membered ring optionally containing afurther nitrogen atom wherein the ring is substituted on carbon ornitrogen, by a group selected from phosphonooxy, and C₁₋₄alkyl whichC₁₋₄alkyl is substituted by phosphonooxy or —NR⁸R⁹ and where the ring isoptionally further substituted on carbon or nitrogen, by 1 or 2C₁₋₄alkyl groups; R³ is C₁₋₄alkoxy or hydrogen; R⁴ is phenyl optionallysubstituted by 1 or 2 of fluoro or chloro; R⁵ is hydrogen or methyl; andR⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl; R⁸ is2-phosphonooxyethyl; and R⁹ is hydrogen, methyl or ethyl; or apharmaceutically acceptable salt thereof.
 23. A compound according toclaim 1 wherein: A is a group of formula (a)

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the (CR⁶R⁷) group of formula (I); X is NH;m is 1, 2 or 3; Z is —NR¹R² or a 4- to 7-membered saturated ring linkedvia a carbon atom, containing a nitrogen atom, which ring is substitutedon carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted byphosphonooxy; R¹ and R² together with the nitrogen to which they areattached form a piperidine, pyrrolidine or piperazine ring which issubstituted by a group selected from phosphonooxy, phosphonooxymethyl,2-phosphonooxyethyl and N-ethyl-N-(2-phosphonooxyethyl)aminomethyl andN-(2-phosphonooxyethyl)aminomethyl and where the ring is optionallyfurther substituted by 1 or 2 methyl; R³ is hydrogen; R⁴ is phenyloptionally substituted by 1 or 2 of fluoro or chloro; R⁵ is hydrogen ormethyl; and R⁶ and R⁷ are independently hydrogen, fluoro, chloro ormethyl; or a pharmaceutically acceptable salt thereof.
 24. Apharmaceutical composition comprising a compound according to claim 9 ora pharmaceutically acceptable salt thereof in association with apharmaceutically acceptable diluent or carrier.